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Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth
This study describes the previously unreported intrinsic capacity of poly-L-lysine (PLL) sixth generation (G6) dendrimer molecules to exhibit systemic antiangiogenic activity that could lead to solid tumor growth arrest. The PLL-dendrimer-inhibited tubule formation of SVEC4-10 murine endothelial cells and neovascularization in the chick embryo chick chorioallantoic membrane (CAM) assay. Intravenous administration of the PLL-dendrimer molecules into C57BL/6 mice inhibited vascularisation in Matrigel plugs implanted subcutaneously. Antiangiogenic activity was further evidenced using intravital microscopy of tumors grown within dorsal skinfold window chambers. Reduced vascularization of P22 rat sarcoma implanted in the dorsal window chamber of SCID mice was observed following tail vein administration (i.v.) of the PLL dendrimers. Also, the in vivo toxicological profile of the PLL-dendrimer molecules was shown to be safe at the dose regime studied. The antiangiogenic activity of the PLL dendrimer was further shown to be associated with significant suppression of B16F10 solid tumor volume and delayed tumor growth. Enhanced apoptosis/necrosis within tumors of PLL-dendrimer-treated animals only and reduction in the number of CD31 positive cells were observed in comparison to protamine treatment. This study suggests that PLL-dendrimer molecules can exhibit a systemic antiangiogenic activity that may be used for therapy of solid tumors, and in combination with their capacity to carry other therapeutic or diagnostic agents may potentially offer capabilities for the design of theranostic systems.
Al-Jamal, Khuloud T.; Al-Jamal, Wafa' T.; Akerman, Simon; Podesta, Jennifer E.; Yilmazer, Acelya; Turton, John A.; Bianco, Alberto; Vargesson, Neil; Kanthou, Chryso; Florence, Alexander T.; Tozer, Gillian M.; Kostarelos, Kostas
STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma
Purpose: Glioblastoma multiforme (GBM) is a devastating brain neoplasm that is essentially incurable. Although radiation therapy prolongs survival, GBMs progress within areas of irradiation. Recent studies in invertebrates have shown that STI571 (Gleevec; Novartis, East Hanover, NJ) enhances the cytotoxicity of ionizing radiation. In the present study, the effectiveness of STI571 in combination with radiation was studied in mouse models of GBM. Methods and Materials: Murine GL261 and human D54 GBM cell lines formed tumors in brains and hind limbs of C57BL6 and nude mice, respectively. GL261 and D54 cells were treated with 5 {mu}mol/L of STI571 for 1 h and/or irradiated with 3 Gy. Protein was analyzed by Western immunoblots probed with antibodies to caspase 3, cleaved caspase 3, phospho-Akt, Akt, and platelet-derived growth factor receptor (PDGFR) {alpha} and {beta}. Tumor volumes were assessed in mice bearing GL261 or D54 tumors treated with 21 Gy administered in seven fractionated doses. Histologic sections from STI571-treated mice were stained with phospho-Akt and phospho-PDGFR {beta} antibodies. Kaplan-Meier survival curves were used to study the response of mice bearing intracranial implants of GL261. Results: STI571 penetrated the blood-brain barrier, which resulted in a reduction in phospho-PDGFR in GBM. STI571-induced apoptosis in GBM was significantly enhanced by irradiation. STI571 combined with irradiation induced caspase 3 cleavage in GBM cells. Glioblastoma multiforme response to therapy correlated with an increase in tumor growth delay and survival when STI571 was administered in conjunction with daily irradiation. Conclusion: These findings suggest that STI571 has the potential to augment radiotherapy and thereby improve median survival.
Geng Ling [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Shinohara, Eric T. [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Kim, Dong [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Tan Jiahuai [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Osusky, Kate [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Shyr, Yu [Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN (United States); Hallahan, Dennis E. [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States) and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN (United States) and Vanderbilt-Ingram Cancer Center, Nashville, TN (United States)]. E-mail: firstname.lastname@example.com
An MMP13-Selective Inhibitor Delays Primary Tumor Growth and the Onset of Tumor-Associated Osteolytic Lesions in Experimental Models of Breast Cancer
We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]phenoxy}phenoxy)-5-(2-methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also significantly inhibited subsequent growth. In contrast, no effects of Cmpd-1 were observed on soft organ metastatic burden following intracardiac or mammary fat pad inoculations of MDA-MB-231 and 4T1.2-Luc cells respectively. MMP13 immunostaining of clinical primary breast tumors and experimental mice tumors revealed intra-tumoral and stromal expression in most tumors, and vasculature expression in all. MMP13 was also detected in osteoblasts in clinical samples of breast-to-bone metastases. The data suggest that MMP13-selective inhibitors, which lack musculoskeletal side effects, may have therapeutic potential both in primary breast cancer and cancer-induced bone osteolysis.
Shah, Manisha; Huang, Dexing; Blick, Tony; Connor, Andrea; Reiter, Lawrence A.; Hardink, Joel R.; Lynch, Conor C.; Waltham, Mark; Thompson, Erik W.
Radioprotection in Normal Tissue and Delayed Tumor Growth by Blockade of CD47 Signaling
Radiation-induced damage of normal tissues restricts the therapeutic doses of ionizing radiation that can be delivered to tumors and thereby limits the effectiveness of radiotherapy. Thrombospondin-1 signaling through its cell surface receptor CD47 limits recovery from several types of stress, and mice lacking either gene are profoundly resistant to radiation injury. We describe strategies to protect normal tissues from radiation damage using CD47 or thrombospondin-1 antibodies, a CD47-binding peptide, or antisense suppression of CD47. A morpholino oligonucleotide targeting CD47 confers radioresistance to human endothelial cells in vitro and protects soft tissue, bone marrow, and tumor-associated leukocytes in irradiated mice. In contrast, CD47 suppression in mice bearing melanoma or squamous lung tumors prior to irradiation result in 89% and 71% smaller tumors, respectively. Thus, inhibiting CD47 signaling maintains the viability of normal tissues following irradiation while increasing the radiosensitivity of tumors.
Maxhimer, Justin B.; Soto-Pantoja, David R.; Ridnour, Lisa A; Shih, Hubert B.; DeGraff, William G.; Tsokos, Maria; Wink, David A.; Isenberg, Jeff S.; Roberts, David D.
Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model
Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors.
Sanchez-Macedo, N; Feng, J; Faubert, B; Chang, N; Elia, A; Rushing, E J; Tsuchihara, K; Bungard, D; Berger, S L; Jones, R G; Mak, T W; Zaugg, K
A cytomegalovirus-based vaccine expressing a single tumor-specific CD8+ T-cell epitope delays tumor growth in a murine model of prostate cancer.
Cytomegalovirus (CMV) is a highly immunogenic virus that results in a persistent, life-long infection in the host typically with no ill effects. Certain unique features of CMV, including its capacity to actively replicate in the presence of strong host CMV-specific immunity, may give CMV an advantage compared with other virus-based vaccine delivery platforms. In the present study, we tested the utility of mouse CMV (mCMV)-based vaccines expressing human prostate-specific antigen (PSA) for prostate cancer immunotherapy in double-transgenic mice expressing PSA and HLA-DRB1*1501 (DR2bxPSA F1 mice). We assessed the capacity of 2 mCMV-based vectors to induce PSA-specific CD8 T-cell responses and affect the growth of PSA-expressing Transgenic Adenocarcinoma of the Mouse Prostate tumors (TRAMP-PSA). In the absence of tumor challenge, immunization with mCMV vectors expressing either a H2-D(b)-restricted epitope PSA(65-73) (mCMV/PSA(65-73)) or the full-length gene for PSA (mCMV/PSA(FL)) induced comparable levels of CD8 T-cell responses that increased (inflated) with time. Upon challenge with TRAMP-PSA tumor cells, animals immunized with mCMV/PSA(65-73) had delay of tumor growth and increased PSA-specific CD8 T-cell responses, whereas animals immunized with mCMV/PSA(FL) showed progressive tumor growth and no increase in number of splenic PSA(65-73)-specific T cells. The data show that a prototype CMV-based prostate cancer vaccine can induce an effective antitumor immune response in a "humanized" double-transgenic mouse model. The observation that mCMV/PSA(FL) is not effective against TRAMP-PSA is consistent with our previous findings that HLA-DRB1*1501-restricted immune responses to PSA are associated with suppression of effective CD8 T-cell responses to TRAMP-PSA tumors. PMID:22576344
Klyushnenkova, Elena N; Kouiavskaia, Diana V; Parkins, Christopher J; Caposio, Patrizia; Botto, Sara; Alexander, Richard B; Jarvis, Michael A
The effects of ultra-high dose rate proton irradiation on growth delay in the treatment of human tumor xenografts in nude mice.
The new technology of laser-driven ion acceleration (LDA) has shown the potential for driving highly brilliant particle beams. Laser-driven ion acceleration differs from conventional proton sources by its ultra-high dose rate, whose radiobiological impact should be investigated thoroughly before adopting current clinical dose concepts. The growth of human FaDu tumors transplanted onto the hind leg of nude mice was measured sonographically. Tumors were irradiated with 20 Gy of 23 MeV protons at pulsed mode with single pulses of 1 ns duration or continuous mode (?100 ms) in comparison to controls and to a dose-response curve for 6 MV photons. Tumor growth delay and the relative biological effectiveness (RBE) were calculated for all irradiation modes. The mean target dose reconstructed from Gafchromic films was 17.4 � 0.8 Gy for the pulsed and 19.7 � 1.1 Gy for the continuous irradiation mode. The mean tumor growth delay was 34 � 6 days for pulsed, 35 � 6 days for continuous protons, and 31 � 7 days for photons 20 � 1.2 Gy, resulting in RBEs of 1.22 � 0.19 for pulsed and 1.10 � 0.18 for continuous protons, respectively. In summary, protons were found to be significantly more effective in reducing the tumor volume than photons (P < 0.05). Together with the results of previous in vitro experiments, the in vivo data reveal no evidence for a substantially different radiobiology that is associated with the ultra-high dose rate of protons that might be generated from advanced laser technology in the future. PMID:24524347
Zlobinskaya, O; Siebenwirth, C; Greubel, C; Hable, V; Hertenberger, R; Humble, N; Reinhardt, S; Michalski, D; R�per, B; Multhoff, G; Dollinger, G; Wilkens, J J; Schmid, T E
Small Interfering RNA Targeted to IGF-IR Delays Tumor Growth and Induces Proinflammatory Cytokines in a Mouse Breast Cancer Model
Insulin-like growth factor I (IGF-I) and its type I receptor (IGF-IR) play significant roles in tumorigenesis and in immune response. Here, we wanted to know whether an RNA interference approach targeted to IGF-IR could be used for specific antitumor immunostimulation in a breast cancer model. For that, we evaluated short interfering RNA (siRNAs) for inhibition of in vivo tumor growth and immunological stimulation in immunocompetent mice. We designed 2?-O-methyl-modified siRNAs to inhibit expression of IGF-IR in two murine breast cancer cell lines (EMT6, C4HD). Cell transfection of IGF-IR siRNAs decreased proliferation, diminished phosphorylation of downstream signaling pathway proteins, AKT and ERK, and caused a G0/G1 cell cycle block. The IGF-IR silencing also induced secretion of two proinflammatory cytokines, TNF- ? and IFN-?. When we transfected C4HD cells with siRNAs targeting IGF-IR, mammary tumor growth was strongly delayed in syngenic mice. Histology of developing tumors in mice grafted with IGF-IR siRNA treated C4HD cells revealed a low mitotic index, and infiltration of lymphocytes and polymorphonuclear neutrophils, suggesting activation of an antitumor immune response. When we used C4HD cells treated with siRNA as an immunogen, we observed an increase in delayed-type hypersensitivity and the presence of cytotoxic splenocytes against wild-type C4HD cells, indicative of evolving immune response. Our findings show that silencing IGF-IR using synthetic siRNA bearing 2?-O-methyl nucleotides may offer a new clinical approach for treatment of mammary tumors expressing IGF-IR. Interestingly, our work also suggests that crosstalk between IGF-I axis and antitumor immune response can mobilize proinflammatory cytokines.
Durfort, Tiphanie; Tkach, Mercedes; Meschaninova, Mariya I.; Rivas, Martin A.; Elizalde, Patricia V.; Venyaminova, Alya G.; Schillaci, Roxana; Francois, Jean-Christophe
Monoclonal Antibodies Targeting Tumor Growth
The type 1 insulin-like growth factor (IGF) receptor (IGF1R) is over-expressed by many tumors and mediates proliferation, motility, and protection from apoptosis. Agents that inhibit IGF1R expression or function can potentially block tumor growth and metastasis. Its major ligands, IGF-I, and IGF-II are over-expressed by multiple tumor types.
How Growth Abnormalities Delay "Puberty" in Drosophila
NSDL National Science Digital Library
In various organisms, including flies, amphibians, and mammals, major developmental transitions such as metamorphosis and puberty are triggered by specific hormones. The requirement for a hormone to proceed to the next stage allows the organism to reestablish the temporal coordination of development between multiple organs that might develop at slightly different rates. Additionally, organisms appear to have evolved mechanisms for delaying these transitions in situations where growth in an organ is abnormal or delayed. New evidence in the fruit fly Drosophila melanogaster indicates that DILP8, a protein of the insulin and relaxin family, delays the onset of metamorphosis under several conditions that alter growth in imaginal discs. Similar mechanisms might operate in disease states in humans where alterations in growth or tissue inflammation can delay puberty.
Iswar K. Hariharan (University of California Berkeley;Department of Molecular and Cell Biology REV)
Periodic and chaotic oscillations in a tumor and immune system interaction model with three delays.
In this paper, a tumor and immune system interaction model consisted of two differential equations with three time delays is considered in which the delays describe the proliferation of tumor cells, the process of effector cells growth stimulated by tumor cells, and the differentiation of immune effector cells, respectively. Conditions for the asymptotic stability of equilibria and existence of Hopf bifurcations are obtained by analyzing the roots of a second degree exponential polynomial characteristic equation with delay dependent coefficients. It is shown that the positive equilibrium is asymptotically stable if all three delays are less than their corresponding critical values and Hopf bifurcations occur if any one of these delays passes through its critical value. Numerical simulations are carried out to illustrate the rich dynamical behavior of the model with different delay values including the existence of regular and irregular long periodic oscillations. PMID:24985415
Bi, Ping; Ruan, Shigui; Zhang, Xinan
Periodic and chaotic oscillations in a tumor and immune system interaction model with three delays
NASA Astrophysics Data System (ADS)
In this paper, a tumor and immune system interaction model consisted of two differential equations with three time delays is considered in which the delays describe the proliferation of tumor cells, the process of effector cells growth stimulated by tumor cells, and the differentiation of immune effector cells, respectively. Conditions for the asymptotic stability of equilibria and existence of Hopf bifurcations are obtained by analyzing the roots of a second degree exponential polynomial characteristic equation with delay dependent coefficients. It is shown that the positive equilibrium is asymptotically stable if all three delays are less than their corresponding critical values and Hopf bifurcations occur if any one of these delays passes through its critical value. Numerical simulations are carried out to illustrate the rich dynamical behavior of the model with different delay values including the existence of regular and irregular long periodic oscillations.
Bi, Ping; Ruan, Shigui; Zhang, Xinan
Mathematical Modeling of Tumor Cell Growth and Immune System Interactions
NASA Astrophysics Data System (ADS)
In this paper, we provide a family of ordinary and delay differential equations to describe the dynamics of tumor-growth and immunotherapy interactions. We explore the effects of adoptive cellular immunotherapy on the model and describe under what circumstances the tumor can be eliminated. The possibility of clearing the tumor, with a strategy, is based on two parameters in the model: the rate of influx of the effector cells, and the rate of influx of IL2. The critical tumor-growth rate, below which endemic tumor does not exist, has been found. One can use the model to make predictions about tumor-dormancy.
Rihan, Fathalla A.; Safan, Muntaser; Abdeen, Mohamed A.; Abdel-Rahman, Duaa H.
CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells
Increased numbers of tumor-infiltrating macrophages correlate with poor disease outcome in patients affected by several types of cancer, including breast and prostate carcinomas. The colony stimulating factor 1 receptor (CSF1R) signaling pathway drives the recruitment of tumor-associated macrophages (TAMs) to the neoplastic microenvironment and promotes the differentiation of TAMs toward a pro-tumorigenic phenotype. Twelve clinical trials are currently evaluating agents that target the CSF1/CSF1R signaling pathway as a treatment against multiple malignancies, including breast carcinoma, leukemia, and glioblastoma. The blockade of CSF1R signaling has been shown to greatly decrease the number of macrophages in a tissue-specific manner. However, additional mechanistic insights are needed in order to understand how macrophages are depleted and the global effects of CSF1R inhibition on other tumor-infiltrating immune cells. Using BLZ945, a highly selective small molecule inhibitor of CSF1R, we show that CSF1R inhibition attenuates the turnover rate of TAMs while increasing the number of CD8+ T cells that infiltrate cervical and breast carcinomas. Specifically, we find that BLZ945 decreased the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. Furthermore, we show that BLZ945 prevents tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis. Our results demonstrate that TAMs undergo a constant turnover in a CSF1R-dependent manner, and suggest that continuous inhibition of the CSF1R pathway may be essential to maintain efficacious macrophage depletion as an anticancer therapy.
Strachan, Debbie C; Ruffell, Brian; Oei, Yoko; Bissell, Mina J; Coussens, Lisa M; Pryer, Nancy; Daniel, Dylan
Carbidopa abrogates L-dopa decarboxylase coactivation of the androgen receptor and delays prostate tumor progression.
The androgen receptor (AR) plays a central role in prostate cancer progression to the castration-resistant (CR) lethal state. L-Dopa decarboxylase (DDC) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells, where it may enhance AR activity. Here, we hypothesize that the DDC enzymatic inhibitor, carbidopa, can suppress DDC-coactivation of AR and retard prostate tumor growth. Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen (PSA) mRNA levels. Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays. The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells (stably expressing AR). In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated ?2-fold in LNCaP xenografts, inducibly overexpressing DDC, were reverted to control levels with carbidopa administration. In castrated mice, treating LNCaP tumors, expressing endogenous DDC, with carbidopa delayed progression to the CR state from 6 to 10 weeks, while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold, respectively. Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors, decrease serum PSA, reduce tumor growth and delay CR progression. Since carbidopa is clinically approved, it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression. PMID:21780103
Wafa, Latif A; Cheng, Helen; Plaa, Nathan; Ghaidi, Fariba; Fukumoto, Takahiro; Fazli, Ladan; Gleave, Martin E; Cox, Michael E; Rennie, Paul S
Delay-induced state transition and resonance in periodically driven tumor model with immune surveillance
NASA Astrophysics Data System (ADS)
The phenomenon of stochastic resonance (SR) in a tumor growth model under the presence of immune surveillance is investigated. Time delay and cross-correlation between multiplicative and additive noises are considered in the system. The signal-to-noise ratio (SNR) is calculated when periodic signal is introduced multiplicatively. Our results show that: (i) the time delay can accelerate the transition from the state of stable tumor to that of extinction, however the correlation between two noises can accelerate the transition from the state of extinction to that of stable tumor; (ii) the time delay and correlation between two noises can lead to a transition between SR and double SR in the curve of SNR as a function of additive noise intensity, however for the curve of SNR as a function of multiplicative noise intensity, the time delay can cause the SR phenomenon to disappear, and the cross-correlation between two noises can lead to a transition from SR to stochastic reverse-resonance. Finally, we compare the SR phenomenon for the multiplicative periodic signal with that for additive periodic signal in the tumor growth model with immune surveillance.
Yang, Tao; Han, Qinglin; Zeng, Chunhua; Wang, Hua; Fu, Yunchang; Zhang, Chun
Netrin-4 Delays Colorectal Cancer Carcinomatosis by Inhibiting Tumor Angiogenesis
A close relationship between tumor angiogenesis, growth, and carcinomatosis has been observed. Netrin-4 (NT-4) has been shown to regulate angiogenic responses. We aimed to examine the effects of NT-4 on colon tumor angiogenesis, growth, and carcinomatosis. We showed that NT-4 was expressed in human colon cancer cells (LS174). A 20-fold increase in NT-4 expression was stably induced by NT-4 pcDNA in LS174 cells. In vivo, a Matrigel angiogenesis assay showed that NT-4 overexpression altered vascular endothelial growth factor (VEGF)/basic fibroblast growth factor�induced angiogenesis. In nude mice with LS174 xenografts, NT-4 overexpression inhibited tumor angiogenesis and growth. In addition, these NT-4-involved inhibitory effects were associated with decreased tumor cell proliferation and increased tumor cell apoptosis. Using an orthotopic peritoneal carcinomatosis model, we demonstrated that NT-4 overexpression decreased colorectal cancer carcinomatosis. Moreover, carcinomatosis-related ascites formation was significantly decreased in mice transplanted with NT-4 LS174 cells versus control LS174 cells. The antiangiogenic activity of NT-4 was probably mediated by binding to its receptor neogenin. Netrin-4 had a direct effect on neither in vitro apoptosis and proliferation of cultured LS174 cells nor the VEGF-induced acute increase in vascular permeability in vivo. We propose that NT-4 overexpression decreases tumor growth and carcinomatosis, probably via an antiangiogenic effect, underlying the potential therapeutic interest in NT-4 in the treatment of colorectal cancer growth and carcinomatosis.
Eveno, Clarisse; Broqueres-You, Dong; Feron, Jean-Guillaume; Rampanou, Aurore; Tijeras-Raballand, Annemilai; Ropert, Stanislas; Leconte, Laurence; Levy, Bernard I.; Pocard, Marc
A Multiscale Model for Avascular Tumor Growth
The desire to understand tumor complexity has given rise to mathematical models to describe the tumor microenvironment. We present a new mathematical model for avascular tumor growth and development that spans three distinct scales. At the cellular level, a lattice Monte Carlo model describes cellular dynamics (proliferation, adhesion, and viability). At the subcellular level, a Boolean network regulates the expression
Y. Jiang; Jelena Pjesivac-Grbovic; Charles Cantrell; James P. Freyer
Brain tumor epidemiology, growth, and invasion.
This article focuses on the most common primary intracranial neoplasms and the biologic descriptions of their growth and invasion. The proliferative aspects of the different primary brain tumors are discussed, along with recently discovered genetic changes. Because local invasion of primary brain tumors is a key pathologic feature of these tumors, the mechanisms known to influence cell movement are discussed. PMID:2135961
Berens, M E; Rutka, J T; Rosenblum, M L
Delayed adolescent growth in homozygous sickle cell disease.
Analysis of the growth abnormalities in sickle cell disease has been limited by the lack of longitudinal observations in individuals, and by an inability to quantitate the observed patterns. To investigate the timing and pattern of the adolescent growth spurt, longitudinal observations of height from the Jamaican cohort study were fitted to a mathematical model of growth (Preece-Baines model 1). The study included 44 children with homozygous sickle cell (SS) disease, 44 age and sex matched subjects with sickle cell haemoglobin C (SC) disease, and 44 age and sex matched controls with normal (AA) haemoglobin. Compared with AA controls, the onset of the adolescent growth spurt was delayed in SS disease by 1.4 years (95% confidence interval 0.8 to 2.0) with no significant sex difference. The age at peak height velocity was delayed by 1.6 years (0.9 to 2.3) in SS compared with AA subjects but the adolescent growth of SS children was otherwise normal and there was no difference in the attained height by age 17.9 years. The growth spurt was not delayed in SC disease. The age at menarche in girls with SS disease (mean (SD) 15.4 (1.3) years) was significantly later than girls with SC disease (13.7 (1.7) years) and those with AA haemoglobin (13.1 (1.3) years) but these genotype differences were no longer significant after controlling for the delay in the adolescent growth spurt. The normally coordinated but slightly delayed pattern of growth and normal adult heights suggests a good prognosis for adolescent growth delay in SS disease. Most children with SS disease can therefore be reassured on the outcome of retarded adolescent growth. PMID:7826110
Singhal, A; Thomas, P; Cook, R; Wierenga, K; Serjeant, G
Adult Height in Girls with Delayed Pubertal Growth
Background\\/Aims: Boys with constitutional delay of growth and puberty (CDGP) with early reduction in relative height before the onset of puberty will have adult height (AH) clearly below their target height (TH). Characteristics of growth in girls with CDGP are poorly known. We examined whether girls with CDGP attain their TH and whether early reduction in height SDS influences their
Karoliina Wehkalampi; Katarina P�kkil�; Tiina Laine; Leo Dunkel
Tumor growth in intestinal neobladder
The case of a 73 years old man with tumor in intestinal neobladder was presented. Tumor was resected using standard TUR technique. Tumor proved to be benign, follow�up revealed no recurrences. The schedule of lifelong follow�up was proposed.
Gluchowski, Jaroslaw; Weli-Wegbe, James; Blawat, Adam; Kordasz, Janusz
MEDI3617, a human anti-angiopoietin 2 monoclonal antibody, inhibits angiogenesis and tumor growth in human tumor xenograft models.
Angiopoietin 2 (Ang2) is an important regulator of angiogenesis, blood vessel maturation and integrity of the vascular endothelium. The correlation between the dynamic expression of Ang2 in tumors with regions of high angiogenic activity and a poor prognosis in many tumor types makes Ang2 an ideal drug target. We have generated MEDI3617, a human anti-Ang2 monoclonal antibody that neutralizes Ang2 by preventing its binding to the Tie2 receptor in vitro, and inhibits angiogenesis and tumor growth in vivo. Treatment of mice with MEDI3617 resulted in inhibition of angiogenesis in several mouse models including: FGF2-induced angiogenesis in a basement extract plug model, tumor and retinal angiogenesis. In xenograft tumor models, treatment with MEDI3617 resulted in a reduction in tumor angiogenesis and an increase in tumor hypoxia. The administration of MEDI3617 as a single agent to mice bearing human tumor xenografts resulted in tumor growth inhibition against a broad spectrum of tumor types. Combining MEDI3617 with chemotherapy or bevacizumab resulted in a delay in tumor growth and no body weight loss was observed in the combination groups. These results, combined with pharmacodynamic studies, demonstrate that treatment of tumor-bearing mice with MEDI3617 significantly inhibited tumor growth as a single agent by blocking tumor angiogenesis. Together, these data show that MEDI3617 is a robust antiangiogenic agent and support the clinical evaluation and biomarker development of MEDI3617 in cancer patients. PMID:22327175
Leow, Ching Ching; Coffman, Karen; Inigo, Ivan; Breen, Shannon; Czapiga, Meggan; Soukharev, Serguei; Gingles, Neill; Peterson, Norman; Fazenbaker, Christine; Woods, Rob; Jallal, Bahija; Ricketts, Sally-Ann; Lavallee, Theresa; Coats, Steve; Chang, Yong
Delayed Contrast Extravasation MRI for Depicting Tumor and Non-Tumoral Tissues in Primary and Metastatic Brain Tumors
The current standard of care for newly diagnosed glioblastoma multiforme (GBM) is resection followed by radiotherapy with concomitant and adjuvant temozolomide. Recent studies suggest that nearly half of the patients with early radiological deterioration post treatment do not suffer from tumor recurrence but from pseudoprogression. Similarly, a significant number of patients with brain metastases suffer from radiation necrosis following radiation treatments. Conventional MRI is currently unable to differentiate tumor progression from treatment-induced effects. The ability to clearly differentiate tumor from non-tumoral tissues is crucial for appropriate patient management. Ten patients with primary brain tumors and 10 patients with brain metastases were scanned by delayed contrast extravasation MRI prior to surgery. Enhancement subtraction maps calculated from high resolution MR images acquired up to 75 min after contrast administration were used for obtaining stereotactic biopsies. Histological assessment was then compared with the pre-surgical calculated maps. In addition, the application of our maps for prediction of progression was studied in a small cohort of 13 newly diagnosed GBM patients undergoing standard chemoradiation and followed up to 19.7 months post therapy. The maps showed two primary enhancement populations: the slow population where contrast clearance from the tissue was slower than contrast accumulation and the fast population where clearance was faster than accumulation. Comparison with histology confirmed the fast population to consist of morphologically active tumor and the slow population to consist of non-tumoral tissues. Our maps demonstrated significant correlation with perfusion-weighted MR data acquired simultaneously, although contradicting examples were shown. Preliminary results suggest that early changes in the fast volumes may serve as a predictor for time to progression. These preliminary results suggest that our high resolution MRI-based delayed enhancement subtraction maps may be applied for clear depiction of tumor and non-tumoral tissues in patients with primary brain tumors and patients with brain metastases.
Zach, Leor; Guez, David; Last, David; Daniels, Dianne; Grober, Yuval; Nissim, Ouzi; Hoffmann, Chen; Nass, Dvora; Talianski, Alisa; Spiegelmann, Roberto; Cohen, Zvi R.; Mardor, Yael
Simulating tumor growth in confined heterogeneous environments
NASA Astrophysics Data System (ADS)
The holy grail of computational tumor modeling is to develop a simulation tool that can be utilized in the clinic to predict neoplastic progression and propose individualized optimal treatment strategies. In order to develop such a predictive model, one must account for many of the complex processes involved in tumor growth. One interaction that has not been incorporated into computational models of neoplastic progression is the impact that organ-imposed physical confinement and heterogeneity have on tumor growth. For this reason, we have taken a cellular automaton algorithm that was originally designed to simulate spherically symmetric tumor growth and generalized the algorithm to incorporate the effects of tissue shape and structure. We show that models that do not account for organ/tissue geometry and topology lead to false conclusions about tumor spread, shape and size. The impact that confinement has on tumor growth is more pronounced when a neoplasm is growing close to, versus far from, the confining boundary. Thus, any clinical simulation tool of cancer progression must not only consider the shape and structure of the organ in which a tumor is growing, but must also consider the location of the tumor within the organ if it is to accurately predict neoplastic growth dynamics.
Gevertz, Jana L.; Gillies, George T.; Torquato, Salvatore
Alpha1-antitrypsin inhibits angiogenesis and tumor growth.
Disturbances of the ratio between angiogenic inducers and inhibitors in tumor microenvironment are the driving force behind angiogenic switch critical for tumor progression. Angiogenic inhibitors may vary depending on organismal age and the tissue of origin. We showed that alpha(1)-antitrypsin (AAT), a serine protease inhibitor (serpin) is an inhibitor of angiogenesis, which induced apoptosis and inhibited chemotaxis of endothelial cells. S- and Z-type mutations that cause abnormal folding and defective serpin activity abrogated AAT antiangiogenic activity. Removal of the C-terminal reactive site loop had no effect on its angiostatic activity. Both native AAT and AAT truncated on C-terminus (AATDelta) inhibited neovascularization in the rat cornea and delayed the growth of subcutaneous tumors in mice. Treatment with native AAT and truncated AATDelta, but not control vehicle reduced tumor microvessel density, while increasing apoptosis within tumor endothelium. Comparative analysis of the human tumors and normal tissues of origin showed correlation between reduced local alpha(1)-antitrypsin expression and more aggressive tumor growth. PMID:15316942
Huang, Hanhua; Campbell, Steven C; Nelius, Thomas; Bedford, Dhugal F; Veliceasa, Dorina; Bouck, Noel P; Volpert, Olga V
Delayed costs of growth and compensatory growth rates
Summary 1. Many studies recognize that growth carries with it a mortality risk that can influence an animal's growth rate. 2. Data suggest that these costs of growth act over a range of time-scales, from instan- taneous to an animal's lifetime. 3. Models of adaptive growth rate have not addressed the issue of differing time-scales over which the costs of
Vascular Endothelial Growth Factor C Promotes Tumor Lymphangiogenesis and Intralymphatic Tumor Growth1
Many solid tumors produce vascular endothelial growth factor C (VEGF-C), and its receptor, VEGFR-3, is expressed in tumor blood vessels. To study the role of VEGF-C in tumorigenesis, we implanted MCF-7 human breast carcinoma cells overexpressing recombinant VEGF-C orthotopically into severe combined immunodeficient mice. VEGF-C increased tumor growth, but unlike VEGF, it had little effect on tumor angiogenesis. Instead, VEGF-C
Terhi Karpanen; Mikala Egeblad; Marika J. Karkkainen; Hajime Kubo; Kari Alitalo
Tumor necrosis factor-alpha promotes tumor growth by inducing vascular endothelial growth factor.
Tumor necrosis factor (TNF)-? has been proved as an adjuvant therapy for tumor by FDA. However, the effect of chronic TNF-? expression for tumor is still controversial. In this study, we investigated the effect of low-dose TNF-? on tumor growth. We confirmed that low-dose TNF-? promoted angiogenesis of tumor in vivo, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1?, the transcription factor of VEGF, were both upregulated. Our results suggested that low-dose TNF-? was a powerful activator of angiogenesis in tumor and HIF-1?-VEGF pathway seemed to be the most important molecular mechanism. PMID:21740086
Jing, Yingying; Ma, Nannan; Fan, Tingting; Wang, Chenyang; Bu, Xinxin; Jiang, Guocheng; Li, Rong; Gao, Lu; Li, Ding; Wu, Mengchao; Wei, Lixin
Chemokines play a paramount role in the tumor progression. Chronic inflammation promotes tumor formation. Both tumor cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumor cell growth, induce angiogenesis and facilitate evasion of immune surveillance through immunoediting. The chemokine receptor CXCR2 and its ligands promote tumor angiogenesis and leukocyte infiltration into the tumor microenvironment. In harsh acidic and hypoxic microenvironmental conditions tumor cells up-regulate their expression of CXCR4, which equips them to migrate up a gradient of CXCL12 elaborated by carcinoma associated fibroblasts (CAFs) to a normoxic microenvironment. The CXCL12-CXCR4 axis facilitates metastasis to distant organs and the CCL21-CCR7 chemokine ligand-receptor pair favors metastasis to lymph nodes. These two chemokine ligand-receptor systems are common key mediators of tumor cell metastasis for several malignancies and as such provide key targets for chemotherapy. In this paper, the role of specific chemokines/chemokine receptor interactions in tumor progression, growth and metastasis and the role of chemokine/chemokine receptor interactions in the stromal compartment as related to angiogenesis, metastasis, and immune response to the tumor are reviewed.
Raman, Dayanidhi; Baugher, Paige J.; Thu, Yee Mon; Richmond, Ann
Growth factors, tumor promoters, and cancer genes
This book contains over 30 selections. Some of the titles are: Growth-regulated genes and human leukemias; Tyrosyl and phosphatidylinositol kinases of human erythrocyte membranes; Growth factors, oncogenes, and multistage carcinogenesis; Tumorigenic transformation of human teratocarcinoma cells by activated ras oncogene but not the homologous photo-oncogene; and Genes that cooperate with tumor promoters in transformation.
Colburn, N.H.; Moses, H.L.; Stanbridge, E.J.
S100A9 Interaction with TLR4 Promotes Tumor Growth
By breeding TRAMP mice with S100A9 knock-out (S100A9?/?) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9?/? and TLR4?/?, but not in RAGE?/? animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGF? expression in splenic CD11b+ cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.
Kallberg, Eva; Vogl, Thomas; Liberg, David; Olsson, Anders; Bjork, Per; Wikstrom, Pernilla; Bergh, Anders; Roth, Johannes; Ivars, Fredrik; Leanderson, Tomas
Modelling population growth with delayed nonlocal reaction in 2-dimensions.
In this paper, we consider the population growth of a single species living in a two-dimensional spatial domain. New reaction-difusion equation models with delayed nonlocal reaction are developed in two-dimensional bounded domains combining diferent boundary conditions. The important feature of the models is the reflection of the joint efect of the difusion dynamics and the nonlocal maturation delayed efect. We consider and ana- lyze numerical solutions of the mature population dynamics with some wellknown birth functions. In particular, we observe and study the occurrences of asymptotically stable steady state solutions and periodic waves for the two-dimensional problems with nonlocal delayed reaction. We also investigate numerically the efects of various parameters on the period, the peak and the shape of the periodic wave as well as the shape of the asymptotically stable steady state solution. PMID:20369915
Liang, Dong; Wu, Jianhong; Zhang, Fan
Super-Rough Dynamics on Tumor Growth
NASA Astrophysics Data System (ADS)
The growth of a cultivated typical brain tumor is studied in this work. The tumor is analyzed both dynamically and morphologically. We have measured its fractal dimension to be df = 1.21+/-0.05. From its dynamical behavior we determine the scaling critical exponents of this circular symmetry system which are compatible with the linear molecular beam epitaxy universality class. A very important feature of tumor profiles is that they are super-rough, which constitutes the first ( 1+1)-dimensional experiment in literature with super-roughness. The results obtained from the dynamics study make manifest two very surprising features of tumor growth: Its dynamics is mainly due to contour cells and the tendency of an interface cell to duplicate is a function of the local curvature.
Br�, Antonio; Pastor, Juan Manuel; Fernaud, Isabel; Br�, Isabel; Melle, Sonia; Berenguer, Carolina
Circulating Fibronectin Controls Tumor Growth12
Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.
von Au, Anja; Vasel, Matthaeus; Kraft, Sabrina; Sens, Carla; Hackl, Norman; Marx, Alexander; Stroebel, Philipp; Hennenlotter, Jorg; Todenhofer, Tilman; Stenzl, Arnulf; Schott, Sarah; Sinn, Hans-Peter; Wetterwald, Antoinette; Bermejo, Justo Lorenzo; Cecchini, Marco G; Nakchbandi, Inaam A
Immunotherapy of Epithelial Tumors Using Intralesional Injection of Antigens that Induce a Delayed Type Hypersensitivity Reaction.
National Technical Information Service (NTIS)
The pharmaceutical composition is useful for treating epithelial tumors in a subject and contains at least two antigens and a pharmaceutically acceptable carrier, where each of the antigens induces or is capable of inducing a cutaneous delayed type hypers...
T. D. Horn S. M. Johnson
Contour Instabilities in Early Tumor Growth Models
NASA Astrophysics Data System (ADS)
Recent tumor growth models are often based on the multiphase mixture framework. Using bifurcation theory techniques, we show that such models can give contour instabilities. Restricting to a simplified but realistic version of such models, with an elastic cell-to-cell interaction and a growth rate dependent on diffusing nutrients, we prove that the tumor cell concentration at the border acts as a control parameter inducing a bifurcation with loss of the circular symmetry. We show that the finite wavelength at threshold has the size of the proliferating peritumoral zone. We apply our predictions to melanoma growth since contour instabilities are crucial for early diagnosis. Given the generality of the equations, other relevant applications can be envisaged for solving problems of tissue growth and remodeling.
Ben Amar, M.; Chatelain, C.; Ciarletta, P.
Supradiaphragmatic ectopic liver: delayed traumatic hepatic hernia mimics pulmonary tumor.
We present a rare case of a 63-year-old woman, the oldest one in the literature, with supradiaphragmatic ectopic liver that mimics a pulmonary nodule. The chest roentgenogram and chest computer tomography showed a lobulated tumor nearby the diaphragm. Pathological examination of the resected tumor disclosed only remarkable fatty liver change. Ectopic liver should be kept in mind to differentiate for the pulmonary tumor nearby the diaphragm. PMID:17546566
Huang, C-S; Hsu, W-H; Hsia, C-Y
Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression
SUMMARY Neoantigens derived from somatic mutations in tumors may provide a critical link between the adaptive immune system and cancer. Here we describe a system to introduce exogenous antigens into genetically engineered mouse lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors.
DuPage, Michel; Cheung, Ann; Mazumdar, Claire; Winslow, Monte M.; Bronson, Roderick; Schmidt, Leah M.; Crowley, Denise; Chen, Jianzhu; Jacks, Tyler
Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice.
Glioblastoma multiforme (GBM) ranks among the deadliest types of cancer and given these new therapies are urgently needed. To identify molecular targets, we queried a microarray profiling 467 human GBMs and discovered that polo-like kinase 1 (PLK1) was highly expressed in these tumors and that it clustered with the proliferative subtype. Patients with PLK1-high tumors were more likely to die from their disease suggesting that current therapies are inactive against such tumors. This prompted us to examine its expression in brain tumor initiating cells (BTICs) given their association with treatment failure. BTICs isolated from patients expressed 110-470 times more PLK1 than normal human astrocytes. Moreover, BTICs rely on PLK1 for survival because the PLK1 inhibitor BI2536 inhibited their growth in tumorsphere cultures. PLK1 inhibition suppressed growth, caused G(2) /M arrest, induced apoptosis, and reduced the expression of SOX2, a marker of neural stem cells, in SF188 cells. Consistent with SOX2 inhibition, the loss of PLK1 activity caused the cells to differentiate based on elevated levels of glial fibrillary acidic protein and changes in cellular morphology. We then knocked glial fibrillary acidic protein (GFAP) down SOX2 with siRNA and showed that it too inhibited cell growth and induced cell death. Likewise, in U251 cells, PLK1 inhibition suppressed cell growth, downregulated SOX2, and induced cell death. Furthermore, BI2536 delayed tumor growth of U251 cells in an orthotopic brain tumor model, demonstrating that the drug is active against GBM. In conclusion, PLK1 level is elevated in GBM and its inhibition restricts the growth of brain cancer cells. PMID:22415968
Lee, Cathy; Fotovati, Abbas; Triscott, Joanna; Chen, James; Venugopal, Chitra; Singhal, Ash; Dunham, Christopher; Kerr, John M; Verreault, Maite; Yip, Stephen; Wakimoto, Hiroaki; Jones, Chris; Jayanthan, Aarthi; Narendran, Aru; Singh, Sheila K; Dunn, Sandra E
Recruitment of myeloid but not endothelial precursor cells facilitates tumor re-growth after local irradiation
Tumor neovascularization and growth may be promoted by recruitment of bone marrow-derived cells (BMDCs), which include endothelial precursor cells (EPCs) and �vascular modulatory� myelomonocytic (CD11b+) cells. BMDCs may also drive tumor re-growth after certain chemotherapeutic and vascular disruption treatments. In this study, we evaluated the role of BMDC recruitment in breast and lung carcinoma xenograft models after local irradiation (LI). We depleted the bone marrow by including whole body irradiation (WBI) of 6Gy as part of a total tumor dose of 21Gy, and compared the growth delay with the one achieved after LI of 21Gy. In both models, including WBI induced longer tumor growth delays. Moreover, including WBI increased lung tumor control probability by LI. Exogenous delivery of BMDCs from radiation-na�ve donors partially abrogated the WBI effect. Myeloid BMDCs, primarily macrophages, rapidly accumulated in tumors after LI. Intratumoral expression of SDF-1?, a chemokine that promotes tissue retention of BMDCs, was noted 2 days after LI. Conversely, treatment with an inhibitor of SDF-1? receptor CXCR4 (AMD3100) with LI significantly delayed tumor re-growth. However, when administered starting from 5 days post-LI, AMD3100 treatment was ineffective. Lastly, with restorative bone marrow transplantation of Tie2-GFP-labeled BMDC population we observed an increased number of monocytes but not EPCs in tumors that recurred following LI. Our results suggest that an increase in intratumoral SDF-1? triggered by local irradiation recruits myelomonocyte/macrophage which promote tumor re-growth.
Kozin, Sergey V.; Kamoun, Walid S.; Huang, Yuhui; Dawson, Michelle R.; Jain, Rakesh K.; Duda, Dan G.
Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis
Tumor-associated stroma is typified by a persistent, non-resolving inflammatory response that enhances tumor angiogenesis, growth and metastasis. Inflammation in tumors is instigated by heterotypic interactions between malignant tumor cells, vascular endothelium, fibroblasts, immune and inflammatory cells. We found that tumor-associated adipocytes also contribute to inflammation. We have analyzed peritumoral adipose tissue in a syngeneic mouse melanoma model. Compared to control adipose tissue, adipose tissue juxtaposed to implanted tumors exhibited reduced adipocyte size, extensive fibrosis, increased angiogenesis and a dense macrophage infiltrate. A mouse cytokine protein array revealed up-regulation of inflammatory mediators including IL-6, CXCL1, MCP-1, MIP-2 and TIMP-1 in peritumoral versus counterpart adipose tissues. CD11b+ macrophages contributed strongly to the inflammatory activity. These macrophages were isolated from peritumoral adipose tissue and found to overexpress ARG1, NOS2, CD301, CD163, MCP-1 and VEGF, which are indicative of both M1 and M2 polarization. Tumors implanted at a site distant from subcutaneous, anterior adipose tissue were strongly growth-delayed, had fewer blood vessels and were less populated by CD11b+ macrophages. In contrast to normal adipose tissue, micro-dissected peritumoral adipose tissue explants launched numerous vascular sprouts when cultured in an ex vivo model. Thus, inflamed tumor-associated adipose tissue fuels the growth of malignant cells by acting as a proximate source for vascular endothelium and activated pro-inflammatory cells, in particular macrophages.
Wagner, Marek; Bjerkvig, Rolf; Wiig, Helge; Melero-Martin, Juan M.; Lin, Ruei-Zeng; Klagsbrun, Michael
Nonlinear simulation of the effect of microenvironment on tumor growth
In this paper, we present and investigate a model for solid tumor growth that incorporates features of the tumor microenvironment. Using analysis and nonlinear numerical simulations, we explore the effects of the interaction between the genetic characteristics of the tumor and the tumor microenvironment on the resulting tumor progression and morphology. We find that the range of morphological responses can
Paul Macklin; John Lowengrub
Radiation-induced changes in the in vivo growth rate of KHT sarcoma cells: implications for the comparison of growth delay and cell survival
A clone size analysis was performed on lung colonies growing from cells derived from subcutaneously growth KHT Sarcomas irradiated in vivo with 0, 1000, 2000 , or 3000 rad of /sup 137/Cs ..gamma.. rays. THe resultant size distributions indicate that the fastest growing colonies (95th percentile of the distribution) have a division delay induced by the radiation which increases with dose at about 2.0 days per 1200 rad. The radiation response of subcutaneously growing KHT Sarcomas was also studied in situ using a growth delay endpoint. A radiation dose of 1500 rad (100-kVp x rays; RBE vs Cs ..gamma.. rays = 1.2) resulted in a growth delay of about 12 days while at 2500 rad this delay increased to about 17 days. Comparison of the results of these two sets of experiments indicates that in this dose range the nonlethal division delay induced by the radiation represents a significant part of the total growth delay observed. The repopulation of the tumor with clonogenic cells following a dose of 2000 rad (100-kVp x rays) was also investigated. An analysis of the results indicated that after the dose of radiation there was an initial small loss (factor of 3 to 4) of clonogenic (presumably hypoxic) cells and that repopulation started about 3 to 4 days after the treatment.
Hill, R.P.
Existence of Limit Cycles in the Solow Model with Delayed-Logistic Population Growth
This paper is devoted to the existence and stability analysis of limit cycles in a delayed mathematical model for the economy growth. Specifically the Solow model is further improved by inserting the time delay into the logistic population growth rate. Moreover, by choosing the time delay as a bifurcation parameter, we prove that the system loses its stability and a Hopf bifurcation occurs when time delay passes through critical values. Finally, numerical simulations are carried out for supporting the analytical results.
Existence of limit cycles in the Solow model with delayed-logistic population growth.
This paper is devoted to the existence and stability analysis of limit cycles in a delayed mathematical model for the economy growth. Specifically the Solow model is further improved by inserting the time delay into the logistic population growth rate. Moreover, by choosing the time delay as a bifurcation parameter, we prove that the system loses its stability and a Hopf bifurcation occurs when time delay passes through critical values. Finally, numerical simulations are carried out for supporting the analytical results. PMID:24592147
Bianca, Carlo; Guerrini, Luca
Essential operating principles for tumor spheroid growth
Background Our objective was to discover in silico axioms that are plausible representations of the operating principles realized during characteristic growth of EMT6/Ro mouse mammary tumor spheroids in culture. To reach that objective we engineered and iteratively falsified an agent-based analogue of EMT6 spheroid growth. EMT6 spheroids display consistent and predictable growth characteristics, implying that individual cell behaviors are tightly controlled and regulated. An approach to understanding how individual cell behaviors contribute to system behaviors is to discover a set of principles that enable abstract agents to exhibit closely analogous behaviors using only information available in an agent's immediate environment. We listed key attributes of EMT6 spheroid growth, which became our behavioral targets. Included were the development of a necrotic core surrounded by quiescent and proliferating cells, and growth data at two distinct levels of nutrient. Results We then created an analogue made up of quasi-autonomous software agents and an abstract environment in which they could operate. The system was designed so that upon execution it could mimic EMT6 cells forming spheroids in culture. Each agent used an identical set of axiomatic operating principles. In sequence, we used the list of targeted attributes to falsify and revise these axioms, until the analogue exhibited behaviors and attributes that were within prespecified ranges of those targeted, thereby achieving a level of validation. Conclusion The finalized analogue required nine axioms. We posit that the validated analogue's operating principles are reasonable representations of those utilized by EMT6/Ro cells during tumor spheroid development.
Engelberg, Jesse A; Ropella, Glen EP; Hunt, C Anthony
Brain Volume in Pediatric Patients with Sickle Cell Disease: Evidence of Volumetric Growth Delay?
BACKGROUND AND PURPOSE: Despite the large body of data available about somatic growth delay in patients with sickle cell disease (SCD), virtually nothing is known about the effect of the disease on volumetric growth of the brain. This study was designed to test a hypothesis that children with SCD have a disease-related delay in brain volumetric growth compared with healthy
R. Grant Steen; Temitope Emudianughe; Michael Hunte; John Glass; Shengjie Wu; Xiaoping Xiong; Wilburn E. Reddick
Potential new way to suppress tumor growth
Researchers at the University of California, San Diego School of Medicine (home of the Moores Comprehensive Cancer Center), with colleagues at the University of Rochester Medical Center, have identified a new mechanism that appears to suppress tumor growth, opening the possibility of developing a new class of anti-cancer drugs. Writing in this week�s online Early Edition of the Proceedings of the National Academy of Sciences (PNAS), the team reports that a particular form of a signaling protein called STAT5A stabilizes the formation of heterochromatin (a form of chromosomal DNA), which in turn suppresses the ability of cancer cells to issue instructions to multiply and grow.
Blocking tumor cell eicosanoid synthesis by GPx4 impedes tumor growth and malignancy
Using tumor cell-restricted overexpression of glutathione peroxidase 4 (GPx4), we investigated the contribution of tumor cell eicosanoids to solid tumor growth and malignant progression in two tumor models differing in tumorigenic potential. By lowering cellular lipid hydroperoxide levels, GPx4 inhibits cyclooxygenase (COX) and lipoxygenase (LOX) activities. GPx4 overexpression drastically impeded solid tumor growth of weakly tumorigenic L929 fibrosarcoma cells, whereas
Ingeborg Heirman; Daisy Ginneberge; Regina Brigelius-Floh�; Nico Hendrickx; Patrizia Agostinis; Peter Brouckaert; Pieter Rottiers; Johan Grooten
Fibroblast growth factors are required for efficient tumor angiogenesis.
Although the function of vascular endothelial growth factor in the induction of tumor angiogenesis is well understood, the role of a second group of angiogenic factors, the fibroblast growth factors (FGFs), remains elusive. We used a recombinant adenovirus expressing soluble FGF receptor (AdsFGFR) to interfere with FGF function in tumor angiogenesis. AdsFGFR repressed endothelial cell proliferation in vitro and inhibited tumor angiogenesis in an ex vivo bioassay, in which endothelial cells were cocultured with angiogenic tumor biopsies in a collagen gel. Moreover, AdsFGFR repressed tumor angiogenesis and hence tumor growth in vivo in allograft transplantation experiments. Whereas adenoviral expression of a soluble form of VEGF receptor 1 (AdsFlt) predominantly affected the initiation of tumor angiogenesis, soluble FGF receptor (sFGFR) appeared to impair the maintenance of tumor angiogenesis. The combination of sFGFR and soluble Flt exhibited a synergistic effect in the repression of tumor growth. Finally, i.v. injection of AdsFGFR resulted in a dramatic repression of tumor growth in a transgenic mouse model of pancreatic beta cell carcinogenesis. Similar to control infections with AdsFlt, tumor-associated vessel density was decreased, indicating that the expression of sFGFR impaired tumor angiogenesis. These data indicate that FGFs play a critical role in tumor angiogenesis. PMID:11156426
Compagni, A; Wilgenbus, P; Impagnatiello, M A; Cotten, M; Christofori, G
The role of complement in tumor growth.
Complement is a central part of the immune system that has developed as a first defense against non-self cells. Neoplastic transformation is accompanied by an increased capacity of the malignant cells to activate complement. In fact, clinical data demonstrate complement activation in cancer patients. On the basis of the use of protective mechanisms by malignant cells, complement activation has traditionally been considered part of the body's immunosurveillance against cancer. Inhibitory mechanisms of complement activation allow cancer cells to escape from complement-mediated elimination and hamper the clinical efficacy of monoclonal antibody-based cancer immunotherapies. To overcome this limitation, many strategies have been developed with the goal of improving complement-mediated effector mechanisms. However, significant work in recent years has identified new and surprising roles for complement activation within the tumor microenvironment. Recent reports suggest that complement elements can promote tumor growth in the context of chronic inflammation. This chapter reviews the data describing the role of complement activation in cancer immunity, which offers insights that may aid the development of more effective therapeutic approaches to control cancer. PMID:24272362
Pio, Ruben; Corrales, Leticia; Lambris, John D
Combination therapy with gefitinib and doxorubicin inhibits tumor growth in transgenic mice with adrenal neuroblastoma
Highly relevant mouse models of human neuroblastoma (NB) are needed to evaluate new therapeutic strategies against NB. In this study, we characterized transgenic mice with bilateral adrenal tumors. On the basis of information from the tumoral gene expression profiles, we examined the antitumor effects of unencapsulated and liposomal doxorubicin (DXR), alone and in combination with gefitinib, on adrenal NB. We showed that intravenous injection of unencapsulated or liposomal DXR alone inhibited tumor growth in a dose-dependent manner, as assessed by magnetic resonance imaging (MRI). However, liposomal DXR did not exhibit greater antitumor effect than unencapsulated DXR. Immunohistochemical analysis revealed that the adrenal tumor vasculature with abundant pericyte coverage was a less leaky structure for liposomes. Combination therapy with unencapsulated or liposomal DXR plus gefitinib strongly suppressed tumor growth and delayed tumor regrowth than treatment with unencapsulated or liposomal DXR alone, even at a lower dose of DXR. Dynamic contrast-enhanced MRI analysis revealed that gefitinib treatment increased blood flow in the tumor, indicating that gefitinib treatment changes the tumor vascular environment in a manner that may increase the antitumor effect of DXR. In conclusion, the combination of gefitinib and DXR induces growth inhibition of adrenal NBs in transgenic mice. These findings will provide helpful insights into new treatments for NB.
Kawano, Kumi; Hattori, Yoshiyuki; Iwakura, Hiroshi; Akamizu, Takashi; Maitani, Yoshie
TGF-?-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth
Tumor-associated macrophages (TAMs) constitute a major component of the immune cell infiltrate observed in the tumor microenvironment (TME). Factors present in the TME, including tumor growth factor-? (TGF-?), allow tumors to circumvent host-mediated immune responses to promote tumor progression. However, the molecular mechanism(s) involved are not clear. Toll-like receptors (TLRs) are important mediators of innate immune responses by immune cells,
T J Standiford; R Kuick; U Bhan; J Chen; M Newstead; V G Keshamouni
Cystemustine induces redifferentiation of primary tumors and confers protection against secondary tumor growth in a melanoma murine model.
N'-(2-Chloroethyl)-N-(2-(methylsulfonyl)-ethyl)-N'-nitrosourea (cystemustine) is a chloroethylnitrosourea that has been used in the treatment of human melanoma. Its main antitumor effect is DNA damage to malignant melanocytes. Although unreported at present, other effects may also account for its cytotoxicity, some of them could be more or less delayed with respect to its administration. In this report, we have developed a model of secondary tumor with B16 melanoma in syngeneic C57B16 recipients to investigate the impact of cystemustine treatment of primary B16 melanoma tumors on the fate of secondary implanted untreated tumors. The data presented in this report indicate that cystemustine-treated cells or the administration of cystemustine provoke an important growth delay of primary melanoma tumors, together with an increase in cell pigmentation and cell morphology changes. Data also show that prime treatment induces a dramatic decrease in tumor weight of secondary untreated tumors accompanied by an increase in melanin content and an alteration of cell morphology. Finally, 1H-NMR spectroscopy was performed on treated B16 cells, showing an alteration in the phospholipid derivatives of melanocytes, suggesting subsequent modifications of membrane phospholipid composition. In conclusion, the data highlight two important findings: (a) cystemustine produces modifications other than DNA damage, i.e., cell morphology changes, pigmentation, and phospholipid metabolism alterations, indicating an interference with cell cycle, cell redifferentiation, and proliferation programs; and (b) cystemustine-treated tumors appear to confer a protective effect against the development of secondary untreated tumors that may be mediated by cytokines or an immune response. PMID:11280801
Demidem, A; Morvan, D; Papon, J; De Latour, M; Madelmont, J C
Reproducible growth in tissue culture of retinoblastoma tumor specimens
Retinoblastoma is a unique embryonic tumor which fre quently arises because of an autosomal dominantly inherited mutation. Study of the genetic changes associated with reti- noblastomas requires techniques that allow proliferation of fresh tumor specimens in tissue culture. However, until the present study, there were no reported methods for routinely obtaining in vitro growth of fresh retinoblastoma tumor cells. When
B L Gallie; Wendy Holmes; Robert A. Phillips
Rare cancers yield potential source of tumor growth
Researchers at the National Institutes of Health have discovered a genetic mutation that appears to increase production of red blood cells in tumors. The discovery, based on analysis of tissue from rare endocrine tumors, may help clarify how some tumors generate a new blood supply to sustain their growth, the researchers explained.
Brick by brick: metabolism and tumor cell growth
Summary Tumor cells display increased metabolic autonomy in comparison to non-transformed cells, taking up nutrients and metabolizing them in pathways that support growth and proliferation. Classical work in tumor cell metabolism focused on bioenergetics, particularly enhanced glycolysis and suppressed oxidative phosphorylation (the �Warburg effect�). But the biosynthetic activities required to create daughter cells are equally important for tumor growth, and recent studies are now bringing these pathways into focus. In this review, we discuss how tumor cells achieve high rates of nucleotide and fatty acid synthesis, how oncogenes and tumor suppressors influence these activities, and how glutamine metabolism enables macromolecular synthesis in proliferating cells.
DeBerardinis, Ralph J.; Sayed, Nabil; Ditsworth, Dara; Thompson, Craig B.
Fibroblast Growth Factors Are Required for Efficient Tumor Angiogenesis1
Although the function of vascular endothelial growth factor in the induction of tumor angiogenesis is well understood, the role of a second group of angiogenic factors, the fibroblast growth factors (FGFs), remains elusive. We used a recombinant adenovirus expressing soluble FGF re- ceptor (AdsFGFR) to interfere with FGF function in tumor angiogenesis. AdsFGFR repressed endothelial cell proliferation in vitro and
Amelia Compagni; Petra Wilgenbus; Maria-Antonietta Impagnatiello; Matt Cotten; Gerhard Christofori
Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis
Extracellular adenosine is a potent immunosuppressor that accumulates during tumor growth. We performed proof-of-concept studies investigating the therapeutic potential and mechanism of action of monoclonal antibody (mAb)-based therapy against CD73, an ecto-enzyme overexpressed on breast-cancer cells that catalyzes the dephosphorylation of adenosine monophosphates into adenosine. We showed that anti-CD73 mAb therapy significantly delayed primary 4T1.2 and E0771 tumor growth in immune-competent mice and significantly inhibited the development of spontaneous 4T1.2 lung metastases. Notably, anti-CD73 mAb therapy was essentially dependent on the induction of adaptive anti-tumor immune responses. Knockdown of CD73 in 4T1.2 tumor cells confirmed the tumor-promoting effects of CD73. In addition to its immunosuppressive effect, CD73 enhanced tumor-cell chemotaxis, suggesting a role for CD73-derived adenosine in tumor metastasis. Accordingly, administration of adenosine-5?-N-ethylcarboxamide to tumor-bearing mice significantly enhanced spontaneous 4T1.2 lung metastasis. Using selective adenosine-receptor antagonists, we showed that activation of A2B adenosine receptors promoted 4T1.2 tumor-cell chemotaxis in vitro and metastasis in vivo. In conclusion, our study identified tumor-derived CD73 as a mechanism of tumor immune escape and tumor metastasis, and it also established the proof of concept that targeted therapy against CD73 can trigger adaptive anti-tumor immunity and inhibit metastasis of breast cancer.
Stagg, John; Divisekera, Upulie; McLaughlin, Nicole; Sharkey, Janelle; Pommey, Sandra; Denoyer, Delphine; Dwyer, Karen M.; Smyth, Mark J.
Assessing growth and response to therapy in murine tumor models.
Rodent models provide an important means of assessing antitumor activity vs toxicity for new cancer therapies. Tumors are often grown subcutaneously on the flank or back of animals, allowing accurate serial determination of tumor volume with calipers by measuring the tumors in three dimensions. The advantages of assessing tumor volume in subcutaneous tumors must be balanced against the potential artifacts induced by growth of tumor cells in subcutaneous tissue. Various orthotopic models have been developed. However, they are more labor-intensive and generally do not allow accurate assessment of tumor growth and/or response unless investigators have access to small animal cross-sectional imaging. Use of small-animal magnetic resonance imaging (MRI) allows one to assess the growth and response of intracavitary tumors, but the cost and labor-intensive nature of MRI limits its use in drug testing. Another approach to intracavitary solid tumor models is the intravenous injection of tumor cells, which can produce lung, liver, or bone metastases (depending on the cell line used), whereas direct injection of tumor cells into the femur or tibia of mice can cause local growth in bone. Progression of both lung metastases and bone lesions can be assessed by small-animal analog X-ray techniques that are more easily available and less labor-intensive to use, and are proving useful for selected therapeutic and biological studies. PMID:15911989
Reynolds, C Patrick; Sun, Bee-Chun; DeClerck, Yves A; Moats, Rex A
Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models1
Abstract The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.
Wu, Yingjen Jeffrey; Muldoon, Leslie L.; Dickey, Dana Thomas; Lewin, Seth J.; Varallyay, Csanad G.; Neuwelt, Edward A.
A Mathematical Model of Prostate Tumor Growth Under Hormone Therapy with Mutation Inhibitor
NASA Astrophysics Data System (ADS)
This paper extends Jackson�s model describing the growth of a prostate tumor with hormone therapy to a new one with hypothetical mutation inhibitors. The new model not only considers the mutation by which androgen-dependent (AD) tumor cells mutate into androgen-independent (AI) ones but also introduces inhibition which is assumed to change the mutation rate. The tumor consists of two types of cells (AD and AI) whose proliferation and apoptosis rates are functions of androgen concentration. The mathematical model represents a free-boundary problem for a nonlinear system of parabolic equations, which describe the evolution of the populations of the above two types of tumor cells. The tumor surface is a free boundary, whose velocity is equal to the cell�s velocity there. Global existence and uniqueness of solutions of this model is proved. Furthermore, explicit formulae of tumor volume at any time t are found in androgen-deprived environment under the assumption of radial symmetry, and therefore the dynamics of tumor growth under androgen-deprived therapy could be predicted by these formulae. Qualitative analysis and numerical simulation show that controlling the mutation may improve the effect of hormone therapy or delay a tumor relapse.
Tao, Youshan; Guo, Qian; Aihara, Kazuyuki
Endothelial cell-derived interleukin-6 regulates tumor growth
Background Endothelial cells play a complex role in the pathobiology of cancer. This role is not limited to the making of blood vessels to allow for influx of oxygen and nutrients required for the high metabolic demands of tumor cells. Indeed, it has been recently shown that tumor-associated endothelial cells secrete molecules that enhance tumor cell survival and cancer stem cell self-renewal. The hypothesis underlying this work is that specific disruption of endothelial cell-initiated signaling inhibits tumor growth. Methods Conditioned medium from primary human dermal microvascular endothelial cells (HDMEC) stably transduced with silencing RNA for IL-6 (or controls) was used to evaluate the role of endothelial-derived IL-6 on the activation of key signaling pathways in tumor cells. In addition, these endothelial cells were co-transplanted with tumor cells into immunodefficient mice to determine the impact of endothelial cell-derived IL-6 on tumor growth and angiogenesis. Results We observed that tumor cells adjacent to blood vessels show strong phosphorylation of STAT3, a key mediator of tumor progression. In search for a possible mechanism for the activation of the STAT3 signaling pathway, we observed that silencing interleukin (IL)-6 in tumor-associated endothelial cells inhibited STAT3 phosphorylation in tumor cells. Notably, tumors vascularized with IL-6-silenced endothelial cells showed lower intratumoral microvessel density, lower tumor cell proliferation, and slower growth than tumors vascularized with control endothelial cells. Conclusions Collectively, these results demonstrate that IL-6 secreted by endothelial cells enhance tumor growth, and suggest that cancer patients might benefit from targeted approaches that block signaling events initiated by endothelial cells.
Vascular Endothelial Growth Factor C-Induced Lymphangiogenesis DecreasesTumor Interstitial Fluid Pressure and Tumor Growth1
Characteristically, most solid tumors exhibit an increased tumor interstitial fluid pressure (TIFP) that directly contributes to the lowered uptake of macromolecular therapeutics into the tumor interstitium. Abnormalities in the tumor-associated lymph vessels are a central brick in the development and prolonged sustaining of an increased TIFP. In the current study, vascular endothelial growth factor C (VEGF-C) was used to enhance tumor-associated lymphangiogenesis as a new mechanism to actively reduce the TIFP by increased lymphatic drainage of the tumor tissue. Human A431 epidermoid vulva carcinoma cells were inoculated in NMRI nu/nu mice to generate a xenograft mouse model. Seven days after tumor cell injection, VEGF-C was peritumorally injected to induce lymphangiogenesis. Tumor growth and TIFP was lowered significantly over time in VEGF-C-treated tumors in comparison to control or VEGF-A-treated animals. These data demonstrate for the first time that actively induced lymphangiogenesis can lower the TIFP in a xenograft tumor model and apparently reduce tumor growth. This model represents a novel approach to modulate biomechanical properties of the tumor interstitium enabling a lowering of TIFP in vivo.
Hofmann, Matthias; Pflanzer, Ralph; Zoller, Nadja Nicole; Bernd, August; Kaufmann, Roland; Thaci, Diamant; Bereiter-Hahn, Jurgen; Hirohata, Satoshi; Kippenberger, Stefan
A two-phase mixture model of avascular tumor growth
NASA Astrophysics Data System (ADS)
Interactions with biological environment surrounding a growing tumor have major influence on tumor invasion. By recognizing that mechanical behavior of tumor cells could be described by biophysical laws, the research on physical oncology aims to investigate the inner workings of cancer invasion. In this study, we introduce a mathematical model of avascular tumor growth using the continuum theory of mixtures. Mechanical behavior of the tumor and physical interactions between the tumor and host tissue are represented by biophysically founded relationships. In this model, a solid tumor is embedded in inviscid interstitial fluid. The tumor has viscous mechanical properties. Interstitial fluid exhibits properties of flow through porous medium. Associated with the mixture saturation constraint, we introduce a Lagrange multiplier which represents hydrostatic pressure of the interstitial fluid. We solved the equations using Finite Element Method in two-dimensions. As a result, we have introduced a two-phase mixture model of avascular tumor growth that provided a flexible mathematical framework to include cells' response to mechanical aspects of the tumor microenvironment. The model could be extended to capture tumor-ECM interactions which would have profound influence on tumor invasion.
Ozturk, Deniz; Burcin Unlu, M.; Yonucu, Sirin; Cetiner, Ugur
BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors.
Bone morphogenetic protein 4 (BMP4) has potential as an anticancer agent. Recent studies have suggested that BMP4 inhibits the survival of cancer stem cells (CSCs) of neural and colon cancers. Here, we showed that BMP4 paracrinically inhibited tumor angiogenesis via the induction of Thrombospondin-1 (TSP1), and consequently suppressed tumor growth in vivo. Although HeLa (human cervical cancer), HCI-H460-LNM35 (highly metastatic human lung cancer) and B16 (murine melanoma) cells did not respond to the BMP4 treatment in vitro, the growth of xeno- and allografts of these cells was suppressed via reductions in tumor angiogenesis after intraperitoneal treatment with BMP4. When we assessed the mRNA expression of major angiogenesis-related factors in grafted tumors, we found that the expression of TSP1 was significantly upregulated by BMP4 administration. We then confirmed that BMP4 was less effective in suppressing the tumor growth of TSP1-knockdown cancer cells. Furthermore, we found that BMP4 reduced vascular endothelial growth factor (VEGF) expression in vivo in a TSP1-dependent manner, which indicates that BMP4 interfered with the stabilization of tumor angiogenesis. In conclusion, the BMP4/TSP1 loop paracrinically suppressed tumor angiogenesis in the tumor microenvironment, which subsequently reduced the growth of tumors. BMP4 may become an antitumor agent and open a new field of antiangiogenic therapy. PMID:24013228
Tsuchida, R; Osawa, T; Wang, F; Nishii, R; Das, B; Tsuchida, S; Muramatsu, M; Takahashi, T; Inoue, T; Wada, Y; Minami, T; Yuasa, Y; Shibuya, M
Second hand smoke stimulates tumor angiogenesis and growth
Exposure to second hand smoke (SHS) is believed to cause lung cancer. Pathological angiogenesis is a requisite for tumor growth. Lewis lung cancer cells were injected subcutaneously into mice, which were then exposed to sidestream smoke (SHS) or clean room air and administered vehicle, cerivastatin, or mecamylamine. SHS significantly increased tumor size, weight, capillary density, VEGF and MCP-1 levels, and
Bo-qing Zhu; Christopher Heeschen; Richard E. Sievers; Joel S. Karliner; William W. Parmley; John P. Cooke
Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors
Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.
Hua Chiaho, E-mail: firstname.lastname@example.com [Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (United States); Wu Shengjie [Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)] [Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (United States); Chemaitilly, Wassim [Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)] [Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee (United States); Lukose, Renin C.; Merchant, Thomas E. [Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)] [Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)
Akt deficiency delays tumor progression, vascular invasion, and distant metastases in a murine model of thyroid cancer
Akt activation is common in progressive thyroid cancer. In breast cancer, Akt1 induced primary cancer growth, but is reported to inhibit metastasis in vivo in several model systems. In contrast, clinical and in vitro studies suggest a metastasis-promoting role for Akt1 in thyroid cancer. The goal of this study was to determine the functional role of Akt1 in thyroid cancer growth and metastatic progression in vivo using thyroid hormone receptor ?PV/PV knock-in (PV) mice which develop metastatic thyroid cancer. We crossed Akt1-/- and PV mice and compared tumor development, local progression, metastasis, and histology in TR?PV/PV/Akt1+/+ (PVPV-Akt1WT) and TR?PV/PV/Akt1-/- (PVPV-Akt1KO) mice. Mice were sacrificed at 3, 6, 9, 12, and 15 months; necropsy was performed and serum TSH was measured. Thyroid hyperplasia occurred in both groups beginning at three months; the thyroid size was greater in the PVPV-Akt1WT mice (p<0.001). In comparison with PVPV-Akt1WT mice, thyroid cancer development was delayed in the PVPV-Akt1KO mice (P=0.003) and the degree of tumor invasion was reduced. The PVPV-Akt1WT mice displayed pulmonary metastases at 12 and 15 months of age, by contrast PVPV-Akt1KO mice did not develop distant metastases at 15 months of age. Despite continued expression of Akt2 or Akt3, pAkt levels were decreased, and there was evidence of reduced Akt effect on p27 in the PVPV-Akt1KO thyroids. TSH levels were similarly elevated in PV mice regardless of Akt1 expression. In conclusion, thyroid cancer development and progression in TR?PV/PV mice are Akt1-dependent, consistent with a tumor progression-promoting role in this murine thyroid cancer model.
Saji, Motoyasu; Narahara, Katsunura; McCarty, Samantha K.; Vasko, Vasily V.; La Perle, Krista M.; Porter, Kyle; Jarjoura, David; Lu, Changxue; Cheng, Sheue-Yann; Ringel, Matthew D.
Alcohol promotes mammary tumor growth through activation of VEGF-dependent tumor angiogenesis
Alcohol consumption has been recognized as a risk factor for breast cancer. Experimental studies demonstrate that alcohol exposure promotes the progression of existing mammary tumors. However, the mechanisms underlying this effect remain unclear. In the present study, the role of vascular endothelial growth factor (VEGF) in alcohol promotion of breast cancer development was investigated using a mouse xenograft model of mammary tumors and a three-dimensional (3D) tumor/endothelial cell co-culture system. For the mouse xenograft model, mouse E0771 breast cancer cells were implanted into the mammary fat pad of C57BL6 mice. These mice were exposed to alcohol in their drinking water. For the 3D co-culture system, E0771 cells and MDA-MB231 breast cancer cells were co-cultured with SVEC4-10EE2 and human umbilical vein endothelial cells, respectively. The results demonstrated that alcohol increased tumor angiogenesis and accelerated tumor growth. Furthermore, it appeared that alcohol induced VEGF expression in breast cancer cells in vitro and in vivo. Blocking VEGF signaling by SU5416 inhibited tumor angiogenesis in the 3D tumor/endothelial cell co-culture system. Furthermore, injection of SU5416 into mice inhibited alcohol-promoted mammary tumor growth in vivo. These results indicate that alcohol may promote mammary tumor growth by stimulating VEGF-dependent angiogenesis.
Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors.
Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1-inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4(Luc+) cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis. PMID:21415165
Lou, Yuanmei; McDonald, Paul C; Oloumi, Arusha; Chia, Stephen; Ostlund, Christina; Ahmadi, Ardalan; Kyle, Alastair; Auf dem Keller, Ulrich; Leung, Samuel; Huntsman, David; Clarke, Blaise; Sutherland, Brent W; Waterhouse, Dawn; Bally, Marcel; Roskelley, Calvin; Overall, Christopher M; Minchinton, Andrew; Pacchiano, Fabio; Carta, Fabrizio; Scozzafava, Andrea; Touisni, Nadia; Winum, Jean-Yves; Supuran, Claudiu T; Dedhar, Shoukat
Patient specific tumor growth prediction using multimodal images.
Personalized tumor growth model is valuable in tumor staging and therapy planning. In this paper, we present a patient specific tumor growth model based on longitudinal multimodal imaging data including dual-phase CT and FDG-PET. The proposed Reaction-Advection-Diffusion model is capable of integrating cancerous cell proliferation, infiltration, metabolic rate and extracellular matrix biomechanical response. To bridge the model with multimodal imaging data, we introduce Intracellular Volume Fraction (ICVF) measured from dual-phase CT and Standardized Uptake Value (SUV) measured from FDG-PET into the model. The patient specific model parameters are estimated by fitting the model to the observation, which leads to an inverse problem formalized as a coupled Partial Differential Equations (PDE)-constrained optimization problem. The optimality system is derived and solved by the Finite Difference Method. The model was evaluated by comparing the predicted tumors with the observed tumors in terms of average surface distance (ASD), root mean square difference (RMSD) of the ICVF map, average ICVF difference (AICVFD) of tumor surface and tumor relative volume difference (RVD) on six patients with pathologically confirmed pancreatic neuroendocrine tumors. The ASD between the predicted tumor and the reference tumor was 2.4�0.5mm, the RMSD was 4.3�0.4%, the AICVFD was 2.6�0.6%, and the RVD was 7.7�1.3%. PMID:24607911
Liu, Yixun; Sadowski, Samira M; Weisbrod, Allison B; Kebebew, Electron; Summers, Ronald M; Yao, Jianhua
Bioavailable copper modulates oxidative phosphorylation and growth of tumors
Copper is an essential trace element, the imbalances of which are associated with various pathological conditions, including cancer, albeit via largely undefined molecular and cellular mechanisms. Here we provide evidence that levels of bioavailable copper modulate tumor growth. Chronic exposure to elevated levels of copper in drinking water, corresponding to the maximum allowed in public water supplies, stimulated proliferation of cancer cells and de novo pancreatic tumor growth in mice. Conversely, reducing systemic copper levels with a chelating drug, clinically used to treat copper disorders, impaired both. Under such copper limitation, tumors displayed decreased activity of the copper-binding mitochondrial enzyme cytochrome c oxidase and reduced ATP levels, despite enhanced glycolysis, which was not accompanied by increased invasiveness of tumors. The antiproliferative effect of copper chelation was enhanced when combined with inhibitors of glycolysis. Interestingly, larger tumors contained less copper than smaller tumors and exhibited comparatively lower activity of cytochrome c oxidase and increased glucose uptake. These results establish copper as a tumor promoter and reveal that varying levels of copper serves to regulate oxidative phosphorylation in rapidly proliferating cancer cells inside solid tumors. Thus, activation of glycolysis in tumors may in part reflect insufficient copper bioavailability in the tumor microenvironment.
Ishida, Seiko; Andreux, Penelope; Poitry-Yamate, Carole; Auwerx, Johan; Hanahan, Douglas
DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency.
Previous studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xenograft models derived from primary human tumors. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. Treatment with anti-human DLL4 inhibited the expression of Notch target genes and reduced proliferation of tumor cells. Furthermore, we found that specifically inhibiting human DLL4 in the tumor, either alone or in combination with the chemotherapeutic agent irinotecan, reduced cancer stem cell frequency, as shown by flow cytometric and in vivo tumorigenicity studies. PMID:19664991
Hoey, Timothy; Yen, Wan-Ching; Axelrod, Fumiko; Basi, Jesspreet; Donigian, Lucas; Dylla, Scott; Fitch-Bruhns, Maureen; Lazetic, Sasha; Park, In-Kyung; Sato, Aaron; Satyal, Sanjeev; Wang, Xinhao; Clarke, Michael F; Lewicki, John; Gurney, Austin
A tumor growth inhibitory factor and a tumor growth promoting factor isolated from unfertilized ova of shad (Alosa sapidissima).
In the present study, a cytostatic tumor growth inhibitory peptide and a tumor growth promoting peptide with molecular weights of 20,000-30,000 Da have been identified in the supernatant fraction of unfertilized ova from Shad. The factors can be separated by gel chromatography, thus indicating that the factors are individual molecules. Both of the factors are nondialyzable, heat stable, and resistant to trypsin digestion and periodate oxidation. PMID:2930539
Sheid, B; Prat, J C; Gaetjens, E
Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101.
Histone acetylation has a central role in the control of gene expression, influencing transcriptional control of many genes, including tumor suppressor genes. PXD101 is a novel hydroxamate-type inhibitor of histone deacetylase activity that inhibits histone deacetylase activity in HeLa cell extracts with an IC(50) of 27 nM and induces a concentration-dependent (0.2-5 micro M) increase in acetylation of histone H4 in tumor cell lines. PXD101 is cytotoxic in vitro in a number of tumor cell lines with IC(50)s in the range 0.2-3.4 micro M as determined by a clonogenic assay and induces apoptosis. Treatment of nude mice bearing human ovarian and colon tumor xenografts with PXD101 (10-40 mg/kg/day i.p.) daily for 7 days causes a significant dose-dependent growth delay with no obvious signs of toxicity to the mice. Growth delay is also observed for xenografts of cisplatin-resistant ovarian tumor cells. A marked increase in acetylation of H4 is detected in blood and tumor of mice 3 h after treatment with PXD101. The inhibition of growth of human tumor xenografts in mice, with no apparent toxicity, suggests that PXD101 has potential as a novel antitumor agent. Furthermore, the ability to measure histone acetylation in blood samples could provide a suitable pharmacodynamic end point to monitor drug activity. PMID:12939461
Plumb, Jane A; Finn, Paul W; Williams, Robert J; Bandara, Morwenna J; Romero, M Rosario; Watkins, Claire J; La Thangue, Nicholas B; Brown, Robert
Dual Role of ?6?4 Integrin in Epidermal Tumor Growth: Tumor-suppressive Versus Tumor-promoting Function
An increased expression of the integrin ?6?4 is correlated with a poor prognosis in patients with squamous cell carcinomas. However, little is known about the role of ?6?4 in the early stages of tumor development. We have isolated cells from mouse skin (mouse tumor-initiating cells [mTICs]) that are deficient in both p53 and Smad4 and carry conditional alleles of the ?4 gene (Itgb4). The mTICs display many features of multipotent epidermal stem cells and produce well-differentiated tumors after subcutaneous injection into nude mice. Deletion of Itgb4 led to enhanced tumor growth, indicating that ?6?4 mediates a tumor-suppressive effect. Reconstitution experiments with ?4-chimeras showed that this effect is not dependent on ligation of ?6?4 to laminin-5, but on the recruitment by this integrin of the cytoskeletal linker protein plectin to the plasma membrane. Depletion of plectin, like that of ?4, led to increased tumor growth. In contrast, when mTICs had been further transformed with oncogenic Ras, ?6?4 stimulated tumor growth, as previously observed in human squamous neoplasms. Expression of different effector-loop mutants of RasV12 suggests that this effect depends on a strong activation of the Erk pathway. Together, these data show that depending on the mutations involved, ?6?4 can either mediate an adhesion-independent tumor-suppressive effect or act as a tumor promotor.
Raymond, Karine; Kreft, Maaike; Song, Ji-Ying; Janssen, Hans
A multiphase model for three-dimensional tumor growth
NASA Astrophysics Data System (ADS)
Several mathematical formulations have analyzed the time-dependent behavior of a tumor mass. However, most of these propose simplifications that compromise the physical soundness of the model. Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the thermodynamically constrained averaging theory. A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TCs), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HCs); and an interstitial fluid for the transport of nutrients. The equations are solved by a finite element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry. Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTSs) and tumor cords. First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium. The tumor growth pattern follows a biphasic behavior: initially, the rapidly growing TCs tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time. A core with necrotic cells appears for tumor sizes larger than 150 ?m, surrounded by a shell of viable TCs whose thickness stays almost constant with time. A formula to estimate the size of the necrotic core is proposed. In the second case, the MTS is confined within a healthy tissue. The growth rate is reduced, as compared to the first case�mostly due to the relative adhesion of the TCs and HCs to the ECM, and the less favorable transport of nutrients. In particular, for HCs adhering less avidly to the ECM, the healthy tissue is progressively displaced as the malignant mass grows, whereas TC infiltration is predicted for the opposite condition. Interestingly, the infiltration potential of the tumor mass is mostly driven by the relative cell adhesion to the ECM. In the third case, a tumor cord model is analyzed where the malignant cells grow around microvessels in a three-dimensional geometry. It is shown that TCs tend to migrate among adjacent vessels seeking new oxygen and nutrients. This model can predict and optimize the efficacy of anticancer therapeutic strategies. It can be further developed to answer questions on tumor biophysics, related to the effects of ECM stiffness and cell adhesion on TC proliferation.
Scium�, G.; Shelton, S.; Gray, W. G.; Miller, C. T.; Hussain, F.; Ferrari, M.; Decuzzi, P.; Schrefler, B. A.
RGD-Tachyplesin Inhibits Tumor Growth1
Tachyplesin is an antimicrobial peptide present in leukocytes of the horseshoe crab (Tachypleus tridentatus). In this study, a synthetic tachyplesin conjugated to the integrin homing domain RGD was tested for antitumor activity. The in vitro results showed that RGD-tachyplesin inhibited the proliferation of both cultured tumor and endothelial cells and reduced the colony formation of TSU prostate cancer cells. Staining
Yixin Chen; Xueming Xu; Shuigen Hong; Jinguo Chen; Ningfei Liu; Charles B. Underhill; Karen Creswell; Lurong Zhang
MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis
MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK�/� mice. Transplantation of MerTK�/� bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, MerTK�/� leukocytes exhibited lower tumor cell�induced expression of wound healing cytokines, e.g., IL-10 and growth arrest-specific 6 (GAS6), and enhanced expression of acute inflammatory cytokines, e.g., IL-12 and IL-6. Intratumoral CD8+ T lymphocyte numbers were higher and lymphocyte proliferation was increased in tumor-bearing MerTK�/� mice compared with tumor-bearing wild-type mice. Antibody-mediated CD8+ T lymphocyte depletion restored tumor growth in MerTK�/� mice. These data demonstrate that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies.
Cook, Rebecca S.; Jacobsen, Kristen M.; Wofford, Anne M.; DeRyckere, Deborah; Stanford, Jamie; Prieto, Anne L.; Redente, Elizabeth; Sandahl, Melissa; Hunter, Debra M.; Strunk, Karen E.; Graham, Douglas K.; Earp, H. Shelton
Absence of manganese superoxide dismutase delays p53-induced tumor formation?
Background Manganese superoxide dismutase (MnSOD) is a mitochondrial antioxidant enzyme that is down-regulated in a majority of cancers. Due to this observation, as well as MnSOD's potent antioxidant enzymatic activity, MnSOD has been suggested as a tumor suppressor for over 30 years. However, testing this postulate has proven difficult due to the early post-natal lethality of the MnSOD constitutive knock-out mouse. We have previously used a conditional tissue-specific MnSOD knock-out mouse to study the effects of MnSOD loss on the development of various cell types, but long-term cancer development studies have not been performed. We hypothesized the complete loss of MnSOD would significantly increase the rate of tumor formation in a tissue-specific manner. Results Utilizing a hematopoietic stem cell specific Cre-recombinase mouse model, we created pan-hematopoietic cell MnSOD knock-out mice. Additionally, we combined this MnSOD knock-out with two well established models of lymphoma development: B-lymphocyte specific Myc over-expression and conditional pan-hematopoietic cell p53 knock-out. Mice were allowed to age unchallenged until illness or death had occurred. Contrary to our initial hypothesis, the loss of MnSOD alone was insufficient in causing an increase in tumor formation, but did cause significant life-shortening skin pathology in a strain-dependent manner. Moreover, the loss of MnSOD in conjunction with either Myc overexpression or p53 knock-out did not accelerate tumor formation, and in fact delayed lymphomagenesis in the p53 knock-out model. Conclusions Our findings strongly suggest that MnSOD does not act as a classical tumor suppressor in hematological tissues. Additionally, the complete loss of MnSOD may actually protect from tumor development by the creation of an unfavorable redox environment for tumor progression. In summary, these results in combination with our previous work suggest that MnSOD needs to be tightly regulated for proper cellular homeostasis, and altering the activity in either direction may lead to cellular dysfunction, oncogenesis, or death.
Case, Adam J.; Domann, Frederick E.
TRPV Channels in Tumor Growth and Progression
\\u000a Transient receptor potential (TRP) channels affect several physiological and pathological processes. In particular, TRP channels\\u000a have been recently involved in the triggering of enhanced proliferation, aberrant differentiation, and resistance to apoptotic\\u000a cell death leading to the uncontrolled tumor invasion. About thirty TRPs have been identified to date, and are classified\\u000a in seven different families: TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin),
Giorgio Santoni; Valerio Farfariello; Consuelo Amantini
Three-Dimensional Multispecies Nonlinear Tumor Growth-II: Tumor Invasion and Angiogenesis
We extend the diffuse interface model developed in Wise et al. (2008) to study nonlinear tumor growth in 3D. Extensions include the tracking of multiple viable cell species populations through a continuum diffuse-interface approach, onset and aging of discrete tumor vessels through angiogenesis, and incorporation of individual cell movement using a hybrid continuum-discrete approach. We investigate disease progression as a function of cellular-scale parameters such as proliferation and oxygen/nutrient uptake rates. We find that heterogeneity in the physiologically complex tumor microenvironment, caused by non-uniform distribution of oxygen, cell nutrients, and metabolites, as well as phenotypic changes affecting cellular-scale parameters, can be quantitatively linked to the tumor macro-scale as a mechanism that promotes morphological instability. This instability leads to invasion through tumor infiltration of surrounding healthy tissue. Models that employ a biologically-founded, multiscale approach, as illustrated in this work, could help to quantitatively link the critical effect of heterogeneity in the tumor microenvironment with clinically observed tumor growth and invasion. Using patient tumor-specific parameter values, this approach may provide a predictive tool to characterize the complex in vivo tumor physiological characteristics and clinical response, and thus lead to improved treatment modalities and prognosis.
Frieboes, H.B.; Jin, F.; Chuang, Y.-L.; Wise, S.M.; Lowengrub, J.S.; Cristini, V.
TESTIN suppresses tumor growth and invasion via manipulating cell cycle progression in endometrial carcinoma.
Background The TESTIN gene was demonstrated to be a tumor suppressor in prostate and breast cancer through inhibiting tumor growth and invasion. Herein, we aimed to investigate the detailed functions of TESTIN in the highly sexual hormone (estrogen)-dependent malignancy, endometrial carcinoma. Material and Methods TESTIN mRNA and protein expression were measured by qRT-PCR, Western blot and immunohistochemistry. Upregulation of TESTIN was achieved by transfecting the pcDNA3.1-TESTIN plasmids into AN3CA cells. Knockdown of TESTIN was achieved by transfecting the shRNA-TESTIN into Ishikawa cells. MTT assay, colony formation assay, and Transwell assay were used to investigate the effects of TESTIN on cellular proliferation and invasion. The apoptotic status and cell cycle were analyzed using flow cytometry. MMP2 secretion was determined by ELISA assay. The xenograft assay was used to investigate the functions of TESTIN in nude mice. Results Compared to the non-malignant adjacent endometrium, 54% of tumor samples presented downregulation of TESTIN (P<0.001). Loss of TESTIN protein was correlated with advanced tumor stage (P=0.047), high grade (P=0.034), and lymphatic vascular space invasion (P=0.036). In vitro, overexpression of TESTIN suppressed cell proliferation, induced dramatic G1 arrest, and inhibited tumor invasion through blocking the secretion of MMP2. Loss of TESTIN accelerated cellular proliferation, promoted cell cycle progression, and enhanced tumor invasion by increasing the secretion of MMP2. Consistently, TESTIN could significantly delay the growth of xenografts in nude mice. Conclusions TESTIN was commonly downregulated in human endometrial carcinoma and was associated with poor prognostic markers. Moreover, TESTIN signi?cantly inhibited tumor growth and invasion via arresting cell cycle in in vitro and in vivo experiments. Therefore, we propose that TESTIN might be a prognostic marker and therapeutic target for endometrial carcinoma. PMID:24929083
Gu, Zhenpeng; Ding, Guofeng; Liang, Kuixiang; Zhang, Hongtao; Guo, Guanghong; Zhang, Lili; Cui, Jinxiu
TESTIN suppresses tumor growth and invasion via manipulating cell cycle progression in endometrial carcinoma
Background The TESTIN gene was demonstrated to be a tumor suppressor in prostate and breast cancer through inhibiting tumor growth and invasion. Herein, we aimed to investigate the detailed functions of TESTIN in the highly sexual hormone (estrogen)-dependent malignancy, endometrial carcinoma. Material/Methods TESTIN mRNA and protein expression were measured by qRT-PCR, Western blot and immunohistochemistry. Upregulation of TESTIN was achieved by transfecting the pcDNA3.1-TESTIN plasmids into AN3CA cells. Knockdown of TESTIN was achieved by transfecting the shRNA-TESTIN into Ishikawa cells. MTT assay, colony formation assay, and Transwell assay were used to investigate the effects of TESTIN on cellular proliferation and invasion. The apoptotic status and cell cycle were analyzed using flow cytometry. MMP2 secretion was determined by ELISA assay. The xenograft assay was used to investigate the functions of TESTIN in nude mice. Results Compared to the non-malignant adjacent endometrium, 54% of tumor samples presented downregulation of TESTIN (P<0.001). Loss of TESTIN protein was correlated with advanced tumor stage (P=0.047), high grade (P=0.034), and lymphatic vascular space invasion (P=0.036). In vitro, overexpression of TESTIN suppressed cell proliferation, induced dramatic G1 arrest, and inhibited tumor invasion through blocking the secretion of MMP2. Loss of TESTIN accelerated cellular proliferation, promoted cell cycle progression, and enhanced tumor invasion by increasing the secretion of MMP2. Consistently, TESTIN could significantly delay the growth of xenografts in nude mice. Conclusions TESTIN was commonly downregulated in human endometrial carcinoma and was associated with poor prognostic markers. Moreover, TESTIN significantly inhibited tumor growth and invasion via arresting cell cycle in in vitro and in vivo experiments. Therefore, we propose that TESTIN might be a prognostic marker and therapeutic target for endometrial carcinoma.
Gu, Zhenpeng; Ding, Guofeng; Liang, Kuixiang; Zhang, Hongtao; Guo, Guanghong; Zhang, Lili; Cui, Jinxiu
Inhibition of melanoma tumor growth in vivo by survivin targeting
A role of apoptosis (programmed cell death) in tumor formation and growth was investigated by targeting the apoptosis inhibitor survivin in vivo. Expression of a phosphorylation-defective survivin mutant (Thr34?Ala) triggered apoptosis in several human melanoma cell lines and enhanced cell death induced by the chemotherapeutic drug cisplatin in vitro. Conditional expression of survivin Thr34?Ala in YUSAC2 melanoma cells prevented tumor formation upon s.c. injection into CB.17 severe combined immunodeficient-beige mice. When induced in established melanoma tumors, survivin Thr34?Ala inhibited tumor growth by 60�70% and caused increased apoptosis and reduced proliferation of melanoma cells in vivo. Manipulation of the antiapoptotic pathway maintained by survivin may be beneficial for cancer therapy.
Grossman, Douglas; Kim, Paul J.; Schechner, Jeffrey S.; Altieri, Dario C.
Dispersal, survival and delayed growth of benthic foraminiferal propagules
NASA Astrophysics Data System (ADS)
New data support our previously published propagule dispersal hypothesis and show that propagules of some benthic foraminiferal species can survive for two years before growth commences. Following exposure to simulated shallow-water conditions, shallow-water species of benthic foraminifera appeared and grew in large numbers (commonly >100 ind/12 ml sediment) in the <32 �m-size sediment fraction collected from 320 m water depth in the Skagerrak basin (North Sea). None of the shallow-water species that grew abundantly ( Planorbulina mediterranensis, Morulaeplecta bulbosa, Bolivina pseudoplicata, Cuneata arctica, Eggerelloides scaber, Gavelinopsis praegeri) seem to grow or reproduce at or in the vicinity of the sampling site. Consequently, they must have been transported there as <32 �m-sized individuals. Their sudden appearance when exposed to shallow-water conditions suggests that they had been transported to the sampling site as propagules and that they could survive in the sediments until conditions became suitable for growth and, for some, reproduction. The lack of agglutination on the proloculi of the agglutinated taxa that appeared in the growth-chambers may enhance their passive transport via currents and, thereby, dispersal. Of all the indigenous foraminiferal species that occur at the sampling site, only Textularia earlandi and Bolivinellina pseudopunctata continued to grow and reproduce when transferred from bathyal (320 m) to simulated shallow-water (0 m) conditions. The former is considered a highly opportunistic species. According to the literature, most of the morphospecies which grew in the experiments are cosmopolitan. Our results indicate substantial inter-specific differences in dispersal potential and support previous suggestions that among free-living species, some serial forms have the potential for long-distance dispersal. Still, oceanographic, physical and ecological boundaries and barriers constrain the distribution of most species. In addition to benthic foraminifera, Gromia spp. (rhizarian protists related to the foraminifera) grew in >60% of the experimental growth-chambers.
Alve, Elisabeth; Goldstein, Susan T.
Dispersal, survival and delayed growth of benthic foraminiferal propagules
New data support our previously published propagule dispersal hypothesis and show that propagules of some benthic foraminiferal species can survive for two years before growth commences. Following exposure to simulated shallow-water conditions, shallow-water species of benthic foraminifera appeared and grew in large numbers (commonly >100 ind\\/12ml sediment) in the <32�m-size sediment fraction collected from 320m water depth in the Skagerrak
Elisabeth Alve; Susan T. Goldstein
Immunosuppressive drugs and their effect on experimental tumor growth
The effect of cyclosporin (CyA), FK 506, and mycophenolate mofetil (MPM) on tumor growth was investigated using syngeneic mouse colon carcinoma 38. Mice were laparotomized and the tumor cells were injected into the portal vein to establish liver metastasis. The animals were grouped as follows: groups A-1, B-1, and C-1 were given CyA [15 mg\\/kg body weight (BW)], FK 506
Itsuo Yokoyama; Shuji Hayashi; Takaaki Kobayashi; Motohiko Yasutomi; Kazuharu Uchida; Hiroshi Takagi
From the Cover: Glutamate antagonists limit tumor growth
NASA Astrophysics Data System (ADS)
Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.
Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy
Pharmacological Inhibition of BMK1 Suppresses Tumor Growth Through PML
SUMMARY BMK1 is activated by mitogens and oncogenic signals and, thus, is strongly implicated in tumorigenesis. We found that BMK1 interacted with promyelocytic leukemia protein (PML), and inhibited its tumor-suppressor function through phosphorylation. Furthermore, activated BMK1 notably inhibited PML-dependent activation of p21. To further investigate the BMK-mediated inhibition of the tumor suppressor activity of PML in tumor cells, we developed a small-molecule inhibitor of the kinase activity of BMK1, XMD8-92. Inhibition of BMK1 by XMD8-92 blocked tumor cell proliferation in vitro and significantly inhibited tumor growth in vivo by 95%, demonstrating the efficacy and tolerability of BMK1-targeted cancer treatment in animals.
Yang, Qingkai; Deng, Xianming; Lu, Bingwen; Cameron, Michael; Fearns, Colleen; Patricelli, Matthew P.
[Effect of fenugreek on the growth of different genesis tumors].
This paper deals with antitumor properties of a fenugreek (Trigonella Foenum Graecum L.) as to the different genesis tumors--the Ca755 mouse mammary carcinoma and the Guerin's carcinoma in rats. Fenugreek powder was shown to inhibit (25-40 %) growth of certain tumors, decrease (27-63%) level of malone dialdehyde in liver, heart and kidney. Consumption of fenugreek was accompanied with decreased polyamines (spermine, spermidine, putrescine) content in tumor tissue. Inclusion of fenugreek to allowance was shown to improve certain blood value. PMID:23534282
Zhilenko, V V; Zalietok, S P; Klenov, O O
Optimal control synthesis in therapy of solid tumor growth
NASA Astrophysics Data System (ADS)
A mathematical model of tumor growth therapy is considered. The total amount of a drug is bounded and fixed. The problem is to choose an optimal therapeutic strategy, i.e., to choose an amount of the drug permanently affecting the tumor that minimizes the number of tumor cells by a given time. The problem is solved by the dynamic programming method. Exact and approximate solutions to the corresponding Hamilton-Jacobi-Bellman equation are found. An error estimate is proved. Numerical results are presented.
Bratus', A. S.; Chumerina, E. S.
Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment
The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here we report that neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin (FN) that promote ?5?1 integrin-dependent FN fibril assembly, matrix stiffness, and tumor growth. Tumor growth and FN fibril assembly was reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in FN fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl, that augmented ?5?1 FN fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of FN fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment.
Yaqoob, Usman; Cao, Sheng; Shergill, Uday; Jagavelu, Kumaravelu; Geng, Zhimin; Yin, Meng; de Assuncao, Thiago M; Cao, Ying; Szabolcs, Anna; Thorgeirsson, Snorri; Schwartz, Martin; Yang, Ju Dong; Ehman, Richard; Roberts, Lewis; Mukhopadhyay, Debabrata; Shah, Vijay H.
Semiautomatic growth analysis of multicellular tumor spheroids.
Multicellular tumor spheroids (MCTS) are routinely employed as three-dimensional in vitro models to study tumor biology. Cultivation of MCTS in spinner flasks provides better growing conditions, especially with regard to the availability of nutrients and oxygen, when compared with microtiter plates. The main endpoint of drug response experiments is spheroid size. It is common practice to analyze spheroid size manually with a microscope and an ocular micrometer. This requires removal of some spheroids from the flask, which entails major limitations such as loss of MCTS and the risk of contamination. With this new approach, the authors present an efficient and highly reproducible method to analyze the size of complete MCTS populations in culture containers with transparent, flat bottoms. MCTS sediments are digitally scanned and spheroid volumes are calculated by computerized image analysis. The equipment includes regular office hardware (personal computer, flatbed scanner) and software (Adobe Photoshop, Microsoft Excel, ImageJ). The accuracy and precision of the method were tested using industrial precision steel beads with known diameter. In summary, in comparison with other methods, this approach provides benefits in terms of semiautomation, noninvasiveness, and low costs. PMID:21908797
Rodday, Bjoern; Hirschhaeuser, Franziska; Walenta, Stefan; Mueller-Klieser, Wolfgang
Molecular Cochaperones: Tumor Growth and Cancer Treatment
Molecular chaperones play important roles in all cellular organisms by maintaining the proteome in an optimally folded state. They appear to be at a premium in cancer cells whose evolution along the malignant pathways requires the fostering of cohorts of mutant proteins that are employed to overcome tumor suppressive regulation. To function at significant rates in cells, HSPs interact with cochaperones, proteins that assist in catalyzing individual steps in molecular chaperoning as well as in posttranslational modification and intracellular localization. We review current knowledge regarding the roles of chaperones such as heat shock protein 90 (Hsp90) and Hsp70 and their cochaperones in cancer. Cochaperones are potential targets for cancer therapy in themselves and can be used to assess the likely prognosis of individual malignancies. Hsp70 cochaperones Bag1, Bag3, and Hop play significant roles in the etiology of some cancers as do Hsp90 cochaperones Aha1, p23, Cdc37, and FKBP1. Others such as the J domain protein family, HspBP1, TTC4, and FKBPL appear to be associated with more benign tumor phenotypes. The key importance of cochaperones for many pathways of protein folding in cancer suggests high promise for the future development of novel pharmaceutical agents.
Calderwood, Stuart K.
Maternal MDMA administration in mice leads to neonatal growth delay.
The psychoactive recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is widely abused. The fact that MDMA induces neurotoxic damage in serotonergic nerve endings is well known. However, the effects of MDMA on pregnant and neonatal animals remain unknown. Therefore, we studied the effects of gestational exposure to MDMA on birth, growth, and behavior of pups. Female BALB/c mice were orally administered either water (10 ml/kg) or MDMA (20 mg/10 ml/kg) from gestational day 1 to postnatal day (P) 21. MDMA did not affect the birth rate, but the survival rate of the pups significantly decreased. A significant reduction in body weight gain was observed in pups from MDMA-administered dams during P3-P21. Maternal MDMA treatment caused an attenuated cliff avoidance reaction and decreased motor function in the pups, as determined by the wire hanging test. These results suggest that MDMA treatment during pregnancy and lactation causes growth retardation and dysfunction of motor neurons in mouse pups. PMID:24418707
Kaizaki, Asuka; Tanaka, Sachiko; Yoshida, Takemi; Numazawa, Satoshi
Neuronal Defects and Delayed Wound Healing in Mice Lacking Fibroblast Growth Factor 2
Basic fibroblast growth factor (FGF2) is a wide-spectrum mitogenic, angiogenic, and neurotrophic factor that is expressed at low levels in many tissues and cell types and reaches high concentrations in brain and pituitary. FGF2 has been implicated in a multitude of physiological and pathological processes, including limb development, angiogenesis, wound healing, and tumor growth, but its physiological role is still
Sagrario Ortega; Michael Ittmann; Stephen H. Tsang; Michelle Ehrlich; Claudio Basilico
CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR
Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer.
Wang, Tianxiao; Yang, Jingxuan; Xu, Jianwei; Li, Jian; Cao, Zhe; Zhou, Li; You, Lei; Shu, Hong; Lu, Zhaohui; Li, Huihua; Li, Min; Zhang, Taiping; Zhao, Yupei
Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth
Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect. Phosphoglycerate dehydrogenase (PHDGH) catalyzes the first step of the serine biosynthetic pathway downstream of glycolysis, which is a metabolic gatekeeper both for macromolecular biosynthesis and serine-dependent DNA synthesis. Here, we report that PHDGH is overexpressed in many ER-negative human breast cancer cell lines. PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation. However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent. Our findings suggest that other mechanisms or pathways may bypass exclusive dependence on PHGDH in established human breast cancer xenografts, indicating that PHGDH is dispensable for the growth and maintenance of tumors in vivo.
Chen, Jinyun; Chung, Franklin; Yang, Guizhi; Pu, Minying; Gao, Hui; Jiang, Wei; Yin, Hong; Capka, Vladimir; Kasibhatla, Shailaja; Laffitte, Bryan; Jaeger, Savina; Pagliarini, Raymond; Zhou, Wenlai
Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling.
Mutations in PIK3CA, the gene encoding the p110? catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110? via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CA(H1047R)-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CA(H1047R)-expressing tumors. However, the p110?-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110? and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CA(H1047R). These data suggest that PIK3CA(H1047R)-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110? and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations. PMID:23633485
Young, Christian D; Pfefferle, Adam D; Owens, Philip; Kuba, Mar�a G; Rexer, Brent N; Balko, Justin M; S�nchez, Violeta; Cheng, Hailing; Perou, Charles M; Zhao, Jean J; Cook, Rebecca S; Arteaga, Carlos L
Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases
Transforming growth factor ? (TGF-?) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGF?-inhibitory molecules. We constructed a plasmid encoding a potent TGF-?-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-?. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-? signaling in the liver and to enhance IL-12 -mediated IFN-? production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-? and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2?/?IL2r??/? immunodeficient mice. This effect was associated with downregulation of TGF-? target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-?-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms.
Medina-Echeverz, Jose; Fioravanti, Jessica; Diaz-Valdes, Nancy; Frank, Kathrin; Aranda, Fernando; Gomar, Celia; Ardaiz, Nuria; Dotor, Javier; Umansky, Viktor; Prieto, Jesus; Berraondo, Pedro
DOG1 regulates growth and IGFBP-5 in gastrointestinal stromal tumors
Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor alpha (PDGFRA) which can be therapeutically targeted by tyrosine kinase inhibitors (TKI) such as imatinib. Despite long lasting responses most patients eventually progress after TKI therapy. The calcium-dependent chloride channel DOG1 (ANO1/TMEM16A), which is strongly and specifically expressed in GIST, is used as a diagnostic marker to differentiate GIST from other sarcomas. Here we report that loss of DOG1 expression occurs together with loss of KIT expression in a subset of GIST resistant to KIT inhibitors, and we illustrate the functional role of DOG1 in tumor growth, KIT expression and imatinib response. While DOG1 is a crucial regulator of chloride balance in GIST cells, we found that RNAi-mediated silencing or pharmacological inhibition of DOG1 did not alter cell growth or KIT signaling in vitro. In contrast, DOG1 silencing delayed the growth of GIST xenografts in vivo. Expression profiling of explanted tumors after DOG1 blockade revealed a strong upregulation in the expression of IGFBP5, a potent antiangiogenic factor implicated in tumor suppression. Similar results were obtained after selection of imatinib-resistant DOG1- and KIT-negative cells derived from parental DOG1 and KIT-positive GIST cells, where a 5000-fold increase in IGFBP5 mRNA transcripts were documented. In summary, our findings establish the oncogenic activity of DOG1 in GIST involving modulation of IGF/IGFR signaling in the tumor microenvironment through the antiangiogenic factor IGFBP5.
Simon, Susanne; Grabellus, Florian; Ferrera, Loretta; Galietta, Luis; Schwindenhammer, Benjamin; Muhlenberg, Thomas; Taeger, Georg; Eilers, Grant; Treckmann, Juergen; Breitenbuecher, Frank; Schuler, Martin; Taguchi, Takahiro; Fletcher, Jonathan A.; Bauer, Sebastian
Tumor models for prostate cancer exemplified by fibroblast growth factor 8-induced tumorigenesis and tumor progression.
Prostate cancer is a very common malignancy among Western males. Although most tumors are indolent and grow slowly, some grow and metastasize aggressively. Because prostate cancer growth is usually androgen-dependent, androgen ablation offers a therapeutic option to treat post-resection tumor recurrence or primarily metastasized prostate cancer. However, patients often relapse after the primary response to androgen ablation therapy, and there is no effective cure for cases of castration-resistant prostate cancer (CRPC). The mechanisms of tumor growth in CRPC are poorly understood. Although the androgen receptors (ARs) remain functional in CRPC, other mechanisms are clearly activated (e.g., disturbed growth factor signaling). Results from our laboratory and others have shown that dysregulation of fibroblast growth factor (FGF) signaling, including FGF receptor 1 (FGFR1) activation and FGF8b overexpression, has an important role in prostate cancer growth and progression. Several experimental models have been developed for prostate tumorigenesis and various stages of tumor progression. These models include genetically engineered mice and rats, as well as induced tumors and xenografts in immunodeficient mice. The latter was created using parental and genetically modified cell lines. All of these models greatly helped to elucidate the roles of different genes in prostate carcinogenesis and tumor progression. Recently, patient-derived xenografts have been studied for possible use in testing individual, specific responses of tumor tissue to different treatment options. Feasible and functional CRPC models for drug responsiveness analysis and the development of effective therapies targeting the FGF signaling pathway and other pathways in prostate cancer are being actively investigated. PMID:24607251
Tuomela, Johanna; H�rk�nen, Pirkko
Curcumin inhibits tumor growth and angiogenesis in glioblastoma xenografts.
Among the natural products shown to possess chemopreventive and anticancer properties, curcumin is one of the most potent. In the current study, we investigated the effects of this natural product on the growth of human glioma U-87 cells xenografted into athymic mice. We show here that curcumin administration exerted significant anti-tumor effects on subcutaneous and intracerebral gliomas as demonstrated by the slower tumor growth rate and the increase of animal survival time. While investigating the mechanism of its action in vivo, we observed that curcumin decreased the gelatinolytic activities of matrix metalloproteinase-9. Furthermore, treatment with curcumin inhibited glioma-induced angiogenesis as indicated by the decrease of endothelial cell marker from newly formed vessels and by the diminution of the concentration of hemoglobin in curcumin-treated tumors. We also demonstrate, using an in vitro model of blood-brain barrier, that curcumin can cross the blood-brain barrier to a high level. These are the first results showing that curcumin suppresses tumor growth of gliomas in xenograft models. The mechanisms of the anti-tumor effects of curcumin were related, at least partly, to the inhibition of glioma-induced angiogenesis. PMID:20087857
Perry, Marie-Claude; Demeule, Michel; R�gina, Anthony; Moumdjian, Robert; B�liveau, Richard
Inhibiting Delta-6 Desaturase Activity Suppresses Tumor Growth in Mice
Recent studies have shown that a tumor-supportive microenvironment is characterized by high levels of pro-inflammatory and pro-angiogenic eicosanoids derived from omega-6 (n?6) arachidonic acid (AA). Although the metabolic pathways (COX, LOX, and P450) that generate these n?6 AA eicosanoids have been targeted, the role of endogenous AA production in tumorigenesis remains unexplored. Delta-6 desaturase (D6D) is the rate-limiting enzyme responsible for the synthesis of n?6 AA and increased D6D activity can lead to enhanced n?6 AA production. Here, we show that D6D activity is upregulated during melanoma and lung tumor growth and that suppressing D6D activity, either by RNAi knockdown or a specific D6D inhibitor, dramatically reduces tumor growth. Accordingly, the content of AA and AA-derived tumor-promoting metabolites is significantly decreased. Angiogenesis and inflammatory status are also reduced. These results identify D6D as a key factor for tumor growth and as a potential target for cancer therapy and prevention.
He, Chengwei; Qu, Xiying; Wan, Jianbo; Rong, Rong; Huang, Lili; Cai, Chun; Zhou, Keyuan; Gu, Yan; Qian, Steven Y.; Kang, Jing X.
Hypoxia Promotes Tumor Growth in Linking Angiogenesis to Immune Escape
Despite the impressive progress over the past decade, in the field of tumor immunology, such as the identification of tumor antigens and antigenic peptides, there are still many obstacles in eliciting an effective immune response to eradicate cancer. It has become increasingly clear that tumor microenvironment plays a crucial role in the control of immune protection. Tumors have evolved to utilize hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival, and metastasis. Hypoxia-inducible factor (HIF-1) and vascular endothelial growth factor (VEGF) play a determinant role in promoting tumor cell growth and survival. Hypoxia contributes to immune suppression by activating HIF-1 and VEGF pathways. Accumulating evidence suggests a link between hypoxia and tumor tolerance to immune surveillance through the recruitment of regulatory cells (regulatory T cells and myeloid derived suppressor cells). In this regard, hypoxia (HIF-1? and VEGF) is emerging as an attractive target for cancer therapy. How the microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions will be discussed.
Chouaib, Salem; Messai, Yosra; Couve, Sophie; Escudier, Bernard; Hasmim, Meriem; Noman, Muhammad Zaeem
P-selectin deficiency attenuates tumor growth and metastasis.
Selectins are adhesion receptors that normally recognize certain vascular mucin-type glycoproteins bearing the carbohydrate structure sialyl-Lewisx. The clinical prognosis and metastatic progression of many epithelial carcinomas has been correlated independently with production of tumor mucins and with enhanced expression of sialyl-Lewisx. Metastasis is thought to involve the formation of tumor-platelet-leukocyte emboli and their interactions with the endothelium of distant organs. We provide a link between these observations by showing that P-selectin, which normally binds leukocyte ligands, can promote tumor growth and facilitate the metastatic seeding of a mucin-producing carcinoma. P-selectin-deficient mice showed significantly slower growth of subcutaneously implanted human colon carcinoma cells and generated fewer lung metastases from intravenously injected cells. Three potential pathophysiological mechanisms are demonstrated: first, intravenously injected tumor cells home to the lungs of P-selectin deficient mice at a lower rate; second, P-selectin-deficient mouse platelets fail to adhere to tumor cell-surface mucins; and third, tumor cells lodged in lung vasculature after intravenous injection often are decorated with platelet clumps, and these are markedly diminished in P-selectin-deficient animals. PMID:9689079
Kim, Y J; Borsig, L; Varki, N M; Varki, A
P-selectin deficiency attenuates tumor growth and metastasis
Selectins are adhesion receptors that normally recognize certain vascular mucin-type glycoproteins bearing the carbohydrate structure sialyl-Lewisx. The clinical prognosis and metastatic progression of many epithelial carcinomas has been correlated independently with production of tumor mucins and with enhanced expression of sialyl-Lewisx. Metastasis is thought to involve the formation of tumor-platelet-leukocyte emboli and their interactions with the endothelium of distant organs. We provide a link between these observations by showing that P-selectin, which normally binds leukocyte ligands, can promote tumor growth and facilitate the metastatic seeding of a mucin-producing carcinoma. P-selectin-deficient mice showed significantly slower growth of subcutaneously implanted human colon carcinoma cells and generated fewer lung metastases from intravenously injected cells. Three potential pathophysiological mechanisms are demonstrated: first, intravenously injected tumor cells home to the lungs of P-selectin deficient mice at a lower rate; second, P-selectin-deficient mouse platelets fail to adhere to tumor cell-surface mucins; and third, tumor cells lodged in lung vasculature after intravenous injection often are decorated with platelet clumps, and these are markedly diminished in P-selectin-deficient animals.
Kim, Young J.; Borsig, Lubor; Varki, Nissi M.; Varki, Ajit
Platelet-Derived Growth Factor Production by B16 Melanoma Cells Leads to Increased Pericyte Abundance in Tumors and an Associated Increase in Tumor Growth Rate
Platelet-derived growth factor (PDGF) receptor signaling participates in different processes in solid tumors, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimu- lation of tumor angiogenesis. In the present study, the B16 mouse mela- noma tumor model was used to investigate the functional consequences of paracrine PDGF stimulation of host-derived cells. Production of PDGF-BB or
Masao Furuhashi; Tobias Sjoblom; Alexandra Abramsson; Jens Ellingsen; Patrick Micke; Hong Li; Erika Bergsten-Folestad; Ulf Eriksson; Rainer Heuchel; Christer Betsholtz; Carl-Henrik Heldin; Arne Ostman
Sustained Expression of Early Growth Response Protein1 Blocks Angiogenesis and Tumor Growth
Transient induction of the transcription factor early growth response protein-1 (EGR-1) plays a pivotal role in the transcriptional response of endothelial cells to the angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which are produced by most tumors and are involved in the angiogenic switch. We report here that sustained expression of EGR-1 by
Markus Lucerna; Jiri Pomyje; Diana Mechtcheriakova; Alexandra Kadl; Florian Gruber; Martin Bilban; Yuri Sobanov; Gernot Schabbauer; Johannes Breuss; Oswald Wagner; Markus Bischoff; Matthias Clauss; Erhard Hofer
Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.
IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity. PMID:23345334
Wang, Zhihui; Liu, Jin-Qing; Liu, Zhenzhen; Shen, Rulong; Zhang, Guoqiang; Xu, Jianping; Basu, Sujit; Feng, Youmei; Bai, Xue-Feng
Systemic Par-4 inhibits non-autochthonous tumor growth.
The tumor suppressor protein Par-4 (Prostate apoptosis response-4) is spontaneously secreted by normal and cancer cells. Extracellular Par-4 induces caspase-dependent apoptosis in cancer cell cultures by binding, via its effector SAC domain, to cell surface GRP78 receptor. However, the functional significance of extracellular Par-4/SAC has not been validated in animal models. We show that Par-4/SAC-transgenic mice express systemic Par-4/SAC protein and are resistant to the growth of non-autochthonous tumors. Consistently, secretory Par-4/SAC pro-apoptotic activity can be transferred from these cancer-resistant transgenic mice to cancer-susceptible mice by bone marrow transplantation. Moreover, intravenous injection of recombinant Par-4 or SAC protein inhibits metastasis of cancer cells. Collectively, our findings indicate that extracellular Par-4/SAC is systemically functional in inhibition of tumor growth and metastasis progression, and may merit investigation as a therapy. PMID:21613819
Zhao, Yanming; Burikhanov, Ravshan; Brandon, Jason; Qiu, Shirley; Shelton, Brent J; Spear, Brett; Bondada, Subbarao; Bryson, Scott; Rangnekar, Vivek M
In vivo growth inhibitory effect of Withania somnifera (Ashwagandha) on a transplantable mouse tumor, Sarcoma 180.
Withania somnifera is a medicinal plant used in the treatment of a variety of ailments in the Ayurvedic system. Alcoholic extract of the root of the plant was injected(ip) at daily doses of 200 to 1000 mg/kg body wt for 15 days starting from 24 hr after intradermal inoculation of 5 x 10(5) cells of S-180 in BALB/c mice. Solid tumor growth was monitored for 100 days. Doses of 400 mg/kg and above produced complete regression of tumor after an initial growth, the percentage of complete response (CR) increasing with increasing drug dose. A 55% CR was obtained at 1000 mg/kg drug administration, but this dose also produced some mortality among the animals. A significant increase in the volume doubling time and growth delay was seen when the drug dose was increased from 500 to 750 mg/kg body wt, but further increase in drug dose to 1000 mg/kg did not produce any significant increase in these responses. Cumulative doses of 7.5 to 10 g at daily doses of 500 or 750 mg/kg seems to produce a good response in this tumor. PMID:1512021
Devi, P U; Sharada, A C; Solomon, F E; Kamath, M S
A novel diterpene suppresses CWR22Rv1 tumor growth in vivo through antiproliferation and proapoptosis.
Androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers (PCa). As recurrent tumors restore AR activity independent of hormones, new therapies that abolish AR activity have been sought to prevent or delay the emergence of ablation-resistant disease. Here, we report that a novel abietane diterpene, 6-hydroxy-5,6-dehydrosugiol (HDHS), isolated from the stem bark of Cryptomeria japonica, was a potent AR antagonist in PCa cells. HDHS treatment of androgen-dependent LNCaP and androgen-responsive 22Rv1 cells induced apoptosis as shown by nucleosome release, activation of caspase-3 and caspase-7, and cleavage of poly(ADP-ribose) polymerase accompanied with concomitant up-regulation of tumor suppressor p53. HDHS also decreased the protein expression of cyclins (D1 and E), cyclin-dependent kinases (CDK2, CDK4, and CDK6), and retinoblastoma phosphorylation in PCa cells, which suggest cell cycle arrest in the G(1) phase. Oral administration of HDHS at 0.5 and 2.5 mg/kg once daily for 24 days to 22Rv1 PCa xenografted mice suppressed tumor growth by 22% and 39%, respectively, in association with decreased proliferation and increased apoptosis in tumor cells, which further correlated with increased levels of HDHS in plasma and tumors. Overall, our data suggest that HDHS has potential for use in chemoprevention and chemotherapy of PCa. PMID:18701487
Lin, Feng-Min; Tsai, Chin-Hsien; Yang, Yu-Chih; Tu, Wei-Chun; Chen, Li-Ru; Liang, Yun-Sa; Wang, Sheng-Yang; Shyur, Lie-Fen; Chien, Shih-Chang; Cha, Tai-Lung; Hsiao, Pei-Wen
TGF-?-induced IRAK-M Expression in Tumor Associated Macrophages Regulates Lung Tumor Growth
Tumor associated macrophages (TAMs) constitute a major component of the immune cell infiltrate observed in the tumor microenvironment (TME). Factors present in the TME including TGF-?, allow tumors to circumvent host mediated immune responses to promote tumor progression. However, the molecular mechanism(s) involved are not clear. Toll-like receptors (TLRs) are important mediators of innate immune responses by immune cells, whose activation triggers the production of molecules required for anti-tumoral responses. Interleukin receptor associated kinase (IRAK)-M is an inactive serine/threonine kinase, predominantly expressed in macrophages and is a potent negative regulator of TLR signaling. Here we show that TAMs express significantly higher levels of IRAK-M compared to peritoneal macrophages (PEMs) in a syngeneic mouse model of lung cancer. Subcutaneous implantation of LLC cells in IRAK-M?/? mice resulted in a five-fold reduction in tumor growth, as compared to tumors in wild type animals. Furthermore, compared to WT TAMs, TAMs isolated from IRAK-M?/? mice displayed features of a classically activated (M1) rather than alternatively activated (M2) phenotype, as manifest by greater expression of IL-12, IFN-?, and iNOS. Human lung cancer cells induced IRAK-M expression in human PBMCs when co-cultured together. Tumor cell-induced expression of IRAK-M was dependent on the activation of TGF-? pathway. Similarly, treatment of human PBMCs or mouse macrophage cell line, RAW 264.4, with TGF-?, induced IRAK-M expression. Interestingly, IRAK-M gene expression in 439 human lung adenocarcinoma tumors correlated with poor survival in patients with lung cancer. Together, our data demonstrates that TGF-?-dependent induction of IRAK-M expression is an important, clinically relevant mechanism by which tumors may circumvent anti-tumor responses of macrophages.
Standiford, Theodore J.; Kuick, Rork; Bhan, Urvashi; Chen, Jun; Newstead, Michael; Keshamouni, Venkateshwar G.
Fibrosis in immune control of mammary-tumor growth.
In malignancies, an interruption of growth (dormancy) is sometimes observed. In the immunogenic mammary carcinoma MC2, dormancy followed by regression after a period of growth was observed in 18% of s.c. implants in normal mice. Dormant implants removed for histologic examination were invariably found to be completely surrounded by a highly fibrous stroma. Fibrosis was enhanced in immunized mice, and reduced in immuno-deficient mice. Surgical disruption of the fibrous capsule around dormant tumors early (19 +/- 3 days) in the immune response led more frequently to resumed growth, while later (32 +/- 3 days) disruption of the capsule led more frequently to complete regressions. This showed that fibrous capsules that could destroy tumors could also shield them against well-developed systemic immune mechanisms. PMID:1568799
Vaage, J
Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.
Matrix metalloprotease-1 (MMP1) is an important mediator of tumorigenesis, inflammation and tissue remodeling through its ability to degrade critical matrix components. Recent studies indicate that stromal-derived MMP1 may exert direct oncogenic activity by signaling through protease-activated receptor-1 (PAR1) in carcinoma cells; however, this has not been established in vivo. We generated an Mmp1a knockout mouse to ascertain whether stromal-derived Mmp1a affects tumor growth. Mmp1a-deficient mice are grossly normal and born in Mendelian ratios; however, deficiency of Mmp1a results in significantly decreased growth and angiogenesis of lung tumors. Coimplantation of lung cancer cells with wild-type Mmp1a(+/+) fibroblasts completely restored tumor growth in Mmp1a-deficient animals, highlighting the critical role of stromal-derived Mmp1a. Silencing of PAR1 expression in the lung carcinoma cells phenocopied stromal Mmp1a-deficiency, thus validating tumor-derived PAR1 as an Mmp1a target. Mmp1a secretion is controlled by the ability of its prodomain to facilitate autocleavage, whereas human MMP1 is efficiently secreted because of stable pro- and catalytic domain interactions. Taken together, these data demonstrate that stromal Mmp1a drives in vivo tumorigenesis and provide proof of concept that targeting the MMP1-PAR1 axis may afford effective treatments of lung cancer. PMID:23708660
Foley, C J; Fanjul-Fern�ndez, M; Bohm, A; Nguyen, N; Agarwal, A; Austin, K; Koukos, G; Covic, L; L�pez-Ot�n, C; Kuliopulos, A
TPX2 regulates tumor growth in human cervical carcinoma cells.
The targeting protein for the Xenopus kinesin?like protein 2 (TPX2), a microtubule-associated protein, has been utilized as a tool to evaluate, more precisely, the proliferative behavior of tumor cells. The abnormal expression of�TPX2�in a variety of malignant tumor types has been reported, however less is known about its role in�cervical cancer. In the present study, the association between TPX2 expression and the biological behavior of cervical cancer, was investigated. Immunohistochemistry and RT-PCR were used to detect the expression of�TPX2 in cervical�cancer�tissues. The inhibitory effect of TPX2-siRNA on the growth of SiHa human cervical carcinoma cells was studied in�vitro. TPX2 expression was identified as significantly higher in cervical carcinoma compared with the control, normal cervical tissues. TPX2�siRNA transfected into SiHa cells induced apoptosis and inhibited cell proliferation and invasion. Similar results were obtained by in�vivo transplantation, as TPX2�siRNA transfection significantly reduced tumor growth of the xenograft in nude mice. The results demonstrated that TPX2�is important in the regulation of tumor growth in cervical cancer and therefore may be a potential therapeutic target as a novel treatment strategy. PMID:24718984
Jiang, Peiyue; Shen, Kexin; Wang, Xuerui; Song, Haiqin; Yue, Ying; Liu, Tongjun
'Doubling down' on the autophagy pathway to suppress tumor growth.
In this issue of Genes & Development, Wei and colleagues (pp. 1204-1216) use elegant genetic approaches to simultaneously delete the essential autophagy gene FIP200 (FAK family-interacting protein of 200 kDa) and the signaling adaptor p62/SQSTM1 within established murine tumors, which reveals an unexpected synergism between the autophagy pathway and p62 in driving tumor growth. Intriguingly, these observations suggest that the combined targeting of autophagy and p62 may serve as an effective approach to treat specific cancers. PMID:24888584
Leidal, Andrew M; Debnath, Jayanta
Delayed union of the clavicle treated with plasma rich in growth factors.
Nonunion is an uncommon complication of fracture of the clavicle; it is usually treated surgically. The use of biological treatments in this type of condition is increasingly more common because of their ease of application. Plasma rich in growth factors (PRGF) has been used in delayed healing and in nonunion of fractures. We report a case of delayed union fracture of the clavicle in which biological treatment was chosen before considering surgery. Three percutaneous injections of PRGF, one every 2 weeks, were delivered into the delayed union site. The autologous PGRF used was obtained through the patented PRGF system. Three months after the final dose, computed tomography study showed healing of the bone. The patient regained complete mobility of the shoulder without pain. Currently she is able to carry out all the normal life activities and experiences no pain. PMID:21138228
Seijas, Roberto; Santana-Suarez, Romen Y; Garcia-Balletbo, Montserrat; Cusc�, Xavier; Ares, Oscar; Cugat, Ram�n
Netrin-4 regulates angiogenic responses and tumor cell growth
Netrin-4 is a 628 amino acid basement membrane component that promotes neurite elongation at low concentrations but inhibits neurite extension at high concentrations. There is a growing body of literature suggesting that several molecules, including netrins, are regulators of both neuronal and vascular growth. It is believed that molecules that guide neural growth and development are also involved in regulating morphogenesis of the vascular tree. Further, netrins have recently been implicated in controlling epithelial cell branching morphogenesis in the breast, lung and pancreas. Characterization of purified netrin-4 in in vitro angiogenesis assays demonstrated that netrin-4 markedly inhibits HMVEC migration and tube formation. Moreover, netrin-4 inhibits proliferation of a variety of human tumor cells in vitro. Netrin-4 has only modest effects on proliferation of endothelial and other non-transformed cells. Netrin-4 treatment results in phosphorylation changes of proteins that are known to control cell growth. Specifically, Phospho-Akt-1, Phospho-Jnk-2, and Phospho-c-Jun are reduced in tumor cells that have been treated with netrin-4. Together, these data suggest a potential role for netrin-4 in regulating tumor growth.
Nacht, Mariana; St Martin, Thia B.; Byrne, Ann; Klinger, Katherine W.; Teicher, Beverly A. [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States); Madden, Stephen L. [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States)], E-mail: firstname.lastname@example.com; Jiang, Yide [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States)], E-mail: email@example.com
Reactivation of the Silenced Thyroid Hormone Receptor ? Gene Expression Delays Thyroid Tumor Progression
That a knock-in mouse harboring a dominant-negative thyroid hormone receptor (TR)-? (Thrb) mutation develops metastatic thyroid cancer strongly suggests the involvement of TR? in carcinogenesis. Epigenetic silencing of the THRB gene is common in human cancers. The aim of the present study was to determine how DNA methylation affected the expression of the THRB gene in differentiated thyroid cancer (DTC) and how reexpression of the THRB gene attenuated the cancer phenotypes. We used methylation-specific PCR to examine the expression and promoter methylation of the THRB gene in DTC tissues. Thyroid cancer cells with hypermethylated THRB were treated with the demethylating agents 5?-aza-2?-deoxycytidine (5?-aza-CdR) and zebularine to evaluate their impact on the cancer cell phenotypes. THRB mRNA expression in DTC was 90% lower than in normal controls, and this decrease was associated with a higher tumor/lymph node staging. The promoter methylation level of the THRB gene had a significant negative correlation with the expression level of the THRB gene. Treatment of FTC-236 cells with 5?-aza-CdR or zebularine induced reexpression of the THRB gene and inhibited cell proliferation and migration. FTC-236 cells stably expressing TR? exhibited lower cell proliferation and migration through inhibition of ?-catenin signaling pathways compared with FTC-236 without TR?. 5?-Aza-CdR also led to suppression of tumor growth in an in vivo xenograft model using FTC-236 cells consistent with the cell-based studies. These finding indicate that TR? is a tumor suppressor and could be tested as a potential therapeutic target.
Kim, Won Gu; Zhu, Xuguang; Kim, Dong Wook; Zhang, Lisa; Kebebew, Electron
Characterization of Nocturnal Ultradian Rhythms of Melatonin in Children with Growth Hormone-Dependent and Independent Growth Delay
To assess the existence of a possible nocturnal ultradian rhythm of melatonin in children, we analyzed 28 pediatric patients (mean age, 9.08 6 2.2 yr) with GH-dependent and GH-independent growth delay. Plasma melatonin was measured by RIA in children sampled every 30 min between 2100 - 0900 h. Statistical analysis consisted of cluster analysis to examine the presence of peaks
A. Munoz-Hoyos; R. JALDO; A. MOLINA-CARBALLO; G. ESCAMES; M. MACIAS; J. M. FERNANDEZ-GARCIA; R. J. REITER; D. ACUNA-CASTROVIEJO
Attenuation of tumor growth by honokiol: an evolving role in oncology.
Honokiol may exert significant antineoplastic effects in other systemic tumors besides skin cancers by virtue of modulation of other pathways. For instance, honokiol attenuates tumor growth in mammary malignancies. It mediates its anti-neoplastic role in these tumors by accentuating the phosphorylation of AMPK. As a result, honokiol causes significant mitigation of tumor proliferation and growth. PMID:23337821
Kapoor, S
Stromal Cell�Derived Factor1 Promotes Cell Migration and Tumor Growth of Colorectal Metastasis
In a mouse model of established extrahepatic colo- rectal metastasis, we analyzed whether stromal cell- derived factor (SDF) 1 stimulates tumor cell migration in vitro and angiogenesis and tumor growth in vivo. METHODS: Using chemotaxis chambers, CT26.WT colorectal tumor cell migration was studied under stimulation with different concentrations of SDF-1. To evaluate angiogenesis and tumor growth in vivo, green fluorescent
Otto Kollmar; Kathrin Rupertus; Claudia Scheuer; Bastian Junker; Bettina Tilton; Martin K. Schilling; Michael D. Menger
The role of mechanical forces in tumor growth and therapy.
Tumors generate physical forces during growth and progression. These physical forces are able to compress blood and lymphatic vessels, reducing perfusion rates and creating hypoxia. When exerted directly on cancer cells, they can increase cells' invasive and metastatic potential. Tumor vessels-while nourishing the tumor-are usually leaky and tortuous, which further decreases perfusion. Hypoperfusion and hypoxia contribute to immune evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies, including radiation. In parallel, vessel leakiness together with vessel compression causes a uniformly elevated interstitial fluid pressure that hinders delivery of blood-borne therapeutic agents, lowering the efficacy of chemo- and nanotherapies. In addition, shear stresses exerted by flowing blood and interstitial fluid modulate the behavior of cancer and a variety of host cells. Taming these physical forces can improve therapeutic outcomes in many cancers. PMID:25014786
Jain, Rakesh K; Martin, John D; Stylianopoulos, Triantafyllos
The role of mechanical forces in tumor growth and therapy
Tumors generate physical forces during growth and progression. These physical forces are able to compress blood and lymphatic vessels, reducing perfusion rates and creating hypoxia. When exerted directly on cancer cells, they can increase their invasive and metastatic potential. Tumor vessels - while nourishing the tumor - are usually leaky and tortuous, which further decreases perfusion. Hypo-perfusion and hypoxia contribute to immune-evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies, including radiation. In parallel, vessel leakiness together with vessel compression cause a uniformly elevated interstitial fluid pressure that hinders delivery of blood-borne therapeutic agents, lowering the efficacy of chemo- and nano-therapies. In addition, shear stresses exerted by flowing blood and interstitial fluid modulate the behavior of cancer and a variety of host cells. Taming these physical forces can improve therapeutic outcomes in many cancers.
Jain, Rakesh K.; Martin, John D.; Stylianopoulos, Triantafyllos
Natural killer cells: role in local tumor growth and metastasis
Historically, the name of natural killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the 1970s to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced antitumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis, and their implications in antitumor immunotherapies via cytokines, antibodies, or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed.
Langers, Inge; Renoux, Virginie M; Thiry, Marc; Delvenne, Philippe; Jacobs, Nathalie
Low levels of tumor necrosis factor alpha increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site.
Microenvironmental cues instruct infiltrating tumor-associated myeloid cells to drive malignant progression. A subpopulation of tumor-associated myeloid cells coexpressing endothelial and myeloid markers, although rare in peripheral blood, are primarily associated with tumors where they enhance tumor growth and angiogenesis. These biphenotypic vascular leukocytes result from the endothelial differentiation of myeloid progenitors, a process regulated by tumor necrosis factor (TNF)alpha in vitro. An in vivo increase in tumor-derived TNFalpha expression promoted tumor growth and vascularity of mouse melanoma, lung cancer, and mammary tumors. Notably, tumor growth was accompanied by a significant increase in myeloid/endothelial biphenotypic populations. TNFalpha-associated tumor growth, vascularity, and generation of tumor vascular leukocytes in mouse melanoma tumors were dependent on intact host TNFalpha receptors. Importantly, TNFalpha-expressing tumors did not exhibit increased inflammation over control tumors, suggesting a unique action related to myeloid to endothelial differentiation. Our studies suggest that TNFalpha constitutes a tumor microenvironment signal that biases recruited monocytes toward a proangiogenic/provasculogenic myeloid/endothelial phenotype. PMID:19118019
Li, Bin; Vincent, Alicia; Cates, Justin; Brantley-Sieders, Dana M; Polk, D Brent; Young, Pampee P
Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities.
FAK and FGFR2 signaling pathways play important roles in cancer development, progression and tumor angiogenesis. PHM16 is a novel ATP competitive inhibitor of FAK and FGFR2. To evaluate the therapeutic efficacy of this agent, we examined its anti-angiogenic effect in HUVEC and its anti-tumor effect in different cancer cell lines. We showed PHM16 inhibited endothelial cell viability, adherence and tube formation along with the added ability to induce endothelial cell apoptosis. This compound significantly delayed tumor cell growth. Together, these data showed that inhibition of both FAK and FGFR2 signaling pathways can enhance anti-tumor and anti-angiogenic activities. PMID:24657306
Dao, Pascal; Jarray, Rafika; Smith, Nikaia; Lepelletier, Yves; Coq, Johanne Le; Lietha, Daniel; Hadj-Slimane, R�da; Herbeuval, Jean-Philippe; Garbay, Christiane; Raynaud, Fran�oise; Chen, Huixiong
Delayed growth of glioma by Scutellaria flavonoids involve inhibition of Akt, GSK-3 and NF-?B signaling
Plants of the genus Scutellaria constitute one of the common components of Eastern as well as traditional American medicine against various human diseases, including cancer. In this study, we examined the in vivo anti-glioma activity of a leaf extract of Scutellaria ocmulgee (SocL) while also exploring their potential molecular mechanisms of action. Oral administration of SocL extract delayed the growth of F98 glioma in F344 rats, both in intracranial and subcutaneous tumor models. Immunohistochemistry revealed inhibition of Akt, GSK-3?/? and NF-?B phosphorylation in the subcutaneous tumors following treatment with Scutellaria. The SocL extract as well as the constituent flavonoid wogonin also showed dose- and time-dependent inhibition of Akt, GSK-3?/? and NF-?B in F98 cell cultures in vitro, as determined by western blot analysis. Pharmacologic inhibitors of PI3K and NF-?B also significantly inhibited the in vitro proliferation of F98 glioma cells, indicating the key role of these signaling molecules in the growth of malignant gliomas. Transfection of F98 cells with constitutively active mutant of AKT (AKT/CA), however, did not significantly reverse Scutellaria-mediated inhibition of proliferation, indicating that Scutellaria flavonoids either directly inhibited Akt kinase activity or acted downstream of Akt. In vitro Akt kinase assay demonstrated that the SocL extract or wogonin could indeed bind to Akt and inhibit its kinase activity. This study provides the first in vivo evidence and mechanistic support for anti-glioma activity of Scutellaria flavonoids and has implications in potential usage of Scutellaria flavonoids in adjuvant therapy for malignant tumors, including gliomas.
Joshee, N.; Chinni, S. R.; Rimando, A. M.; Mittal, S.; Sethi, S.; Yadav, A. K.
Inhibitor of growth tumor suppressors in cancer progression
The inhibitor of growth (ING) family of tumor suppressors has five members and is implicated in the control of apoptosis,\\u000a senescence, DNA repair, and cancer progression. However, little is known about ING activity in the regulation of cancer progression.\\u000a ING members and splice variants seem to behave differently with respect to cancer invasion and metastasis. Interaction with\\u000a histone trimethylated at
Brad Piche; Gang Li
Interfacial properties in a discrete model for tumor growth
NASA Astrophysics Data System (ADS)
We propose and study, by means of Monte Carlo numerical simulations, a minimal discrete model for avascular tumor growth, which can also be applied for the description of cell cultures in vitro. The interface of the tumor is self-affine and its width can be characterized by the following exponents: (i) the growth exponent ?=0.32(2) that governs the early time regime, (ii) the roughness exponent ?=0.49(2) related to the fluctuations in the stationary regime, and (iii) the dynamic exponent z=?/??1.49(2), which measures the propagation of correlations in the direction parallel to the interface, e.g., ??t1/z, where ? is the parallel correlation length. Therefore, the interface belongs to the Kardar-Parisi-Zhang universality class, in agreement with recent experiments of cell cultures in vitro. Furthermore, density profiles of the growing cells are rationalized in terms of traveling waves that are solutions of the Fisher-Kolmogorov equation. In this way, we achieved excellent agreement between the simulation results of the discrete model and the continuous description of the growth front of the culture or tumor.
Moglia, Bel�n; Guisoni, Nara; Albano, Ezequiel V.
Triptolide inhibits the growth and metastasis of solid tumors.
Triptolide (TPL), a diterpenoid triepoxide purified from the Chinese herb Tripterygium wilfordii Hook F, was tested for its antitumor properties in several model systems. In vitro, TPL inhibited the proliferation and colony formation of tumor cells at extremely low concentrations (2-10 ng/ml) and was more potent than Taxol. Likewise, in vivo, treatment of mice with TPL for 2-3 weeks inhibited the growth of xenografts formed by four different tumor cell lines (B16 melanoma, MDA-435 breast cancer, TSU bladder cancer, and MGC80-3 gastric carcinoma), indicating that TPL has a broad spectrum of activity against tumors that contain both wild-type and mutant forms of p53. In addition, TPL inhibited experimental metastasis of B16F10 cells to the lungs and spleens of mice. The antitumor effect of TPL was comparable or superior with that of conventional antitumor drugs, such as Adriamycin, mitomycin, and cisplatin. Importantly, tumor cells that were resistant to Taxol attributable to the overexpression of the multidrug resistant gene 1 were still sensitive to the effects of TPL. Studies on cultured tumor cells revealed that TPL induced apoptosis and reduced the expression of several molecules that regulate the cell cycle. Taken together, these results suggest that TPL has several attractive features as a new antitumor agent. PMID:12533674
Yang, Shanmin; Chen, Jinguo; Guo, Zhen; Xu, Xue-Ming; Wang, Luping; Pei, Xu-Fang; Yang, Jing; Underhill, Charles B; Zhang, Lurong
Numerical simulation of hypoxic cell regulation in avascular tumor growth
NASA Astrophysics Data System (ADS)
Avascular tumor is an early stage of tumor which does not have the blood vessels themselves and depends entirely on the cells around them to get the supply of nutrients such as oxygen and glucose. Hypoxia is a condition in which living cells are deprived of oxygen needed to maintain metabolism and growth. In avascular tumor, the hypoxic environment inhibits the cells proliferation and distinguishes the cellular dynamics into proliferative, quiescent and necrotic cells. In this paper, we present a numerical simulation of mathematical model describing these cellular dynamics using Matlab software with R2009a version. The model formulated in the form of one-dimensional parabolic partial differential equations depending on time and space. The discretization is based on forward differential respect to time and central differential respect to space of finite difference approximation. The results of simulation show that the distribution of proliferating, quiescent and necrotic cells within a tumor spheroid with respect to time and the cells regulation under different rates of nutrients consumptions in one-dimensional computational domain. In conclusion, in the hypoxic environment, the proliferative and quiescent cells grow slowly dependent on some parameter changes and the necrotic cells emerged at the tumor core.
Mohd Said, Norfarizan; Ibrahim, Arsmah; Alias, Norma
3D Multi-Cell Simulation of Tumor Growth and Angiogenesis
We present a 3D multi-cell simulation of a generic simplification of vascular tumor growth which can be easily extended and adapted to describe more specific vascular tumor types and host tissues. Initially, tumor cells proliferate as they take up the oxygen which the pre-existing vasculature supplies. The tumor grows exponentially. When the oxygen level drops below a threshold, the tumor cells become hypoxic and start secreting pro-angiogenic factors. At this stage, the tumor reaches a maximum diameter characteristic of an avascular tumor spheroid. The endothelial cells in the pre-existing vasculature respond to the pro-angiogenic factors both by chemotaxing towards higher concentrations of pro-angiogenic factors and by forming new blood vessels via angiogenesis. The tumor-induced vasculature increases the growth rate of the resulting vascularized solid tumor compared to an avascular tumor, allowing the tumor to grow beyond the spheroid in these linear-growth phases. First, in the linear-spherical phase of growth, the tumor remains spherical while its volume increases. Second, in the linear-cylindrical phase of growth the tumor elongates into a cylinder. Finally, in the linear-sheet phase of growth, tumor growth accelerates as the tumor changes from cylindrical to paddle-shaped. Substantial periods during which the tumor grows slowly or not at all separate the exponential from the linear-spherical and the linear-spherical from the linear-cylindrical growth phases. In contrast to other simulations in which avascular tumors remain spherical, our simulated avascular tumors form cylinders following the blood vessels, leading to a different distribution of hypoxic cells within the tumor. Our simulations cover time periods which are long enough to produce a range of biologically reasonable complex morphologies, allowing us to study how tumor-induced angiogenesis affects the growth rate, size and morphology of simulated tumors.
Shirinifard, Abbas; Gens, J. Scott; Zaitlen, Benjamin L.; Poplawski, Nikodem J.; Swat, Maciej; Glazier, James A.
Phosphatase Inhibitors Modulate the Growth-regulatory Effects of Human Tumor Necrosis Factor on Tumor and Normal Cells
ABSTRACT Tumor necrosis factor a (TNF-a) has been shown to inhibit the growth of tumor cells and stimulate the growth of certain normal cells in vitro. The mechanism,by which TNF exerts its cell growth-regulatory effects is not known. In this report, we investigated the effects of phosphatase inhibitors on the cell growth-inhibitory effects of TNF on L-929, a highly sensitive
Klara Tot pul. Sudha Agarwal; Bharat B. Aggarwal
Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth.
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells in cancer patients and tumor-bearing mice that potently inhibits T cell responses. During tumor progression, MDSCs accumulate in several organs, including the tumor tissue. So far, tumor-infiltrating MDSC subpopulations remain poorly explored. In this study, we performed global gene expression profiling of mouse tumor-infiltrating granulocytic and monocytic (MO-MDSC) subsets compared with MDSCs from peripheral blood. RMA-S lymphoma-infiltrating MO-MDSCs not only produced high levels of NO and arginase-1, but also greatly increased levels of chemokines comprising the CCR5 ligands CCL3, CCL4, and CCL5. MO-MDSCs isolated from B16 melanoma and from skin tumor-bearing ret transgenic mice also expressed high levels of CCL3, CCL4, and CCL5. Expression of CCR5 was preferentially detected on regulatory T cells (Tregs). Accordingly, tumor-infiltrating MO-MDSCs directly attracted high numbers of Tregs via CCR5 in vitro. Intratumoral injection of CCL4 or CCL5 increased tumor-infiltrating Tregs, and deficiency of CCR5 led to their profound decrease. Moreover, in CCR5-deficient mice, RMA-S and B16 tumor growth was delayed emphasizing the importance of CCR5 in the control of antitumor immune responses. Overall, our data demonstrate that chemokines secreted by tumor-infiltrating MO-MDSCs recruit high numbers of Tregs revealing a novel suppressive role of MDSCs with potential clinical implications for the development of cancer immunotherapies. PMID:23152559
Schlecker, Eva; Stojanovic, Ana; Eisen, Christian; Quack, Christian; Falk, Christine S; Umansky, Viktor; Cerwenka, Adelheid
Knockdown of RON receptor kinase delays but does not prevent tumor progression while enhancing HGF/MET signaling in pancreatic cancer cell lines.
In this study, the role of RON (receptor originated from nantes) in tumor progression was further investigated in context with MET expression and activity. RON and MET expressions were not detected in an immortalized normal human pancreas cell line (HPNE), but were co-expressed in five of seven pancreatic ductal adenocarcinoma (PDAC) cell lines (PANC-1, BxPC-3, Capan-2, CFPAC-1 and AsPC-1). RON expression was knocked down by an shRNA approach in two PDAC cell lines (BxPC-3 and CFPAC-1) that co-express MET. Knockdown of RON significantly inhibited cell growth, clonogenicity and macrophage stimulating protein (MSP), RON ligand induced invasion by in vitro assays and significantly inhibited tumor growth (P<0.001) and metastasis (P<0.009) in an orthotopic pancreatic cancer mouse model at week 7. However, by week 9, the mice implanted with RON knockdown cells had developed similar size primary tumors and metastases compared with that seen in the control group at week 7. Western blotting and immunohistochemistry analyses showed that MET remains highly expressed in cells and tumor tissues where RON was knocked down. Moreover, knockdown of RON did not prevent hepatocyte growth factor (HGF) stimulated invasion in in vitro Matrigel assays. Treating cells with MSP induced the transphosphorylation of MET, suggesting that signaling may be modulated by relative levels of RON and MET receptors and their corresponding ligands. To this point, HGF treatment of RON knockdown cells caused an increase in intensity and duration of MET signaling, suggesting that MET signaling may compensate for loss of RON signaling. Treatment of cells with an MET inhibitor, PHA-665752, had minimal effects on inhibiting cell growth but significantly inhibited cell invasion induce by ligands for either MET or RON. These results suggest that HGF/MET signaling may have a more important role in tumor cell invasion and metastasis rather than in tumor cell proliferation. This study indicates that specific inhibition of RON delays but does not prevent progression of PDAC. Moreover, specific signaling may be modulated by the interaction of RON and MET receptors. This dynamic interaction of RON and MET in pancreatic cancer cells suggests that dual targeting of both RON and MET will be preferable to inhibition of either target alone. PMID:24100611
Zhao, S; Cao, L; Freeman, J W
The Contributions of HIF-Target Genes to Tumor Growth in RCC
Somatic mutations or loss of expression of tumor suppressor VHL happen in the vast majority of clear cell Renal Cell Carcinoma, and it�s causal for kidney cancer development. Without VHL, constitutively active transcription factor HIF is strongly oncogenic and is essential for tumor growth. However, the contribution of individual HIF-responsive genes to tumor growth is not well understood. In this study we examined the contribution of important HIF-responsive genes such as VEGF, CCND1, ANGPTL4, EGLN3, ENO2, GLUT1 and IGFBP3 to tumor growth in a xenograft model using immune-compromised nude mice. We found that the suppression of VEGF or CCND1 impaired tumor growth, suggesting that they are tumor-promoting genes. We further discovered that the lack of ANGPTL4, EGLN3 or ENO2 expression did not change tumor growth. Surprisingly, depletion of GLUT1 or IGFBP3 significantly increased tumor growth, suggesting that they have tumor-inhibitory functions. Depletion of IGFBP3 did not lead to obvious activation of IGFIR. Unexpectedly, the depletion of IGFIR protein led to significant increase of IGFBP3 at both the protein and mRNA levels. Concomitantly, the tumor growth was greatly impaired, suggesting that IGFBP3 might suppress tumor growth in an IGFIR-independent manner. In summary, although the overall transcriptional activity of HIF is strongly tumor-promoting, the expression of each individual HIF-responsive gene could either enhance, reduce or do nothing to the kidney cancer tumor growth.
Zhang, Ting; Niu, Xiaohua; Liao, Lili; Cho, Eun-Ah; Yang, Haifeng
Effect of delayed treatment with basic fibroblast growth factor on the survival of striatal spiny projection neurons after perinatal hypoxia�ischemia
Recent studies suggest that delayed treatment with growth factors, including basic fibroblast growth factor (bFGF), may protect against neuronal death after brain injury. This delayed protective effect is particularly relevant to hypoxic�ischemic brain injury during the third trimester of pregnancy, since detection of the insult is much more likely once the fetus is born. The effect of delayed growth factor
Dorothy E. Oorschot; Margaret M. Tompkins; Kerry A. Galvin
Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis
Heparan sulfate glycosaminoglycans, present at the cell surface and in the extracellular matrix that surrounds cells, are important mediators of complex biological processes. Furthermore, it is now apparent that cells dynamically regulate the structure of their heparan sulfate �coat� to differentially regulate extracellular signals. In the present study, the importance of sequence information contained within tumor cell-surface heparan sulfate was investigated. Herein, we demonstrate that the heparan sulfate glycosaminoglycan coat present on tumor cells contains bioactive sequences that impinge on tumor-cell growth and metastasis. Importantly, we find that growth promoting as well as growth inhibiting sequences are contained within the polysaccharide coat. Furthermore, we find that the dynamic balance between these distinct polysaccharide populations regulates specific intracellular signal-transduction pathways. This study not only provides a framework for the development of polysaccharide-based anti-cancer molecules but also underscores the importance of understanding a cell's polysaccharide array in addition to its protein complement, to understand how genotype translates to phenotype in this postgenomic age.
Liu, Dongfang; Shriver, Zachary; Venkataraman, Ganesh; El Shabrawi, Yosuf; Sasisekharan, Ram
Inhibition of tumoral cell respiration and growth by nordihydroguaiaretic acid.
The effects of nordihydroguaiaretic acid (NDGA), best known as an inhibitor of lipoxygenase activities, on the culture growth, oxygen consumption, ATP level, viability, and redox state of some electron carriers of intact TA3 and 786A ascites tumor cells have been studied. NDGA inhibited the respiration rate of these two tumor cell lines by preventing electron flow through the respiratory chain. Consequently, ATP levels, cell viability and culture growth rates were decreased. NDGA did not noticeably inhibit electron flow through both cytochrome oxidase and ubiquinone-cytochrome b-c1 complex. Also, the presence of NDGA changed to redox state of NAD(P)+ to a more reduced level, and the redox states of ubiquinone, cytochrome b and cytochromes c + c1 changed to a more oxidized level. These observations suggest that the electron transport in the tumor mitochondria was inhibited by NDGA at the NADH-dehydrogenase-ubiquinone level (energy-conserving site 1). As a consequence, mitochondrial ATP synthesis would be interrupted. This event could be related to the cytotoxic effect of NDGA. PMID:7986205
Pavani, M; Fones, E; Oksenberg, D; Garcia, M; Hernandez, C; Cordano, G; Mu�oz, S; Mancilla, J; Guerrero, A; Ferreira, J
HE4 (WFDC2) gene overexpression promotes ovarian tumor growth.
Selective overexpression of Human epididymal secretory protein E4 (HE4) points to a role in ovarian cancer tumorigenesis but little is known about the role the HE4 gene or the gene product plays. Here we show that elevated HE4 serum levels correlate with chemoresistance and decreased survival rates in EOC patients. HE4 overexpression promoted xenograft tumor growth and chemoresistance against cisplatin in an animal model resulting in reduced survival rates. HE4 displayed responses to tumor microenvironment constituents and presented increased expression as well as nuclear translocation upon EGF, VEGF and Insulin treatment and nucleolar localization with Insulin treatment. HE4 interacts with EGFR, IGF1R, and transcription factor HIF1?. Constructs of antisense phosphorothio-oligonucleotides targeting HE4 arrested tumor growth in nude mice. Collectively these findings implicate increased HE4 expression as a molecular factor in ovarian cancer tumorigenesis. Selective targeting directed towards the HE4 protein demonstrates therapeutic benefits for the treatment of ovarian cancer. PMID:24389815
Moore, Richard G; Hill, Emily K; Horan, Timothy; Yano, Naohiro; Kim, KyuKwang; MacLaughlan, Shannon; Lambert-Messerlian, Geralyn; Tseng, YiTang Don; Padbury, James F; Miller, M Craig; Lange, Thilo S; Singh, Rakesh K
Circulating angiogenic growth factor levels in mice bearing human tumors using Luminex Multiplex technology
Tumor angiogenesis is essential for tumor growth and metastasis formation. Luminex methodology was used to measure the levels of four angiogenic cytokines in cell culture medium and in the plasma of mice bearing human tumors. We obtained plasma and conditioned culture medium from 12 different human tumor cell lines. Tumor necrosis factor-alpha (TNF-f), basic fibroblast growth factor (bFGF), vascular endothelial
Kristan A. Keyes; Larry Mann; Karen Cox; Patti Treadway; Philip Iversen; Yun-Fei Chen; Beverly A. Teicher
DNA Vaccines Designed to Inhibit Tumor Growth by Suppression of Angiogenesis
The development of new blood vessels, i.e. angiogenesis, is a rate-limiting step in the development of tumors since tumor growth is generally limited to 1�2 mm3 in the absence of a blood supply. Thus, the inhibition of tumor growth by attacking the tumor�s vascular supply offers a primary target for antiangiogenic intervention by DNA-based vaccines. Here, we describe two novel
Ralph A. Reisfeld; A. G. Niethammer; Y. Luo; R. Xiang
Arsenic trioxide inhibits tumor cell growth in malignant rhabdoid tumors in vitro and in vivo by targeting overexpressed Gli1.
Rhabdoid tumors are highly aggressive tumors occurring in infants and very young children. Despite multimodal and intensive therapy prognosis remains poor. Molecular analyses have uncovered several deregulated pathways, among them the CDK4/6-Rb-, the WNT- and the Sonic hedgehog (SHH) pathways. The SHH pathway is activated in rhabdoid tumors by GLI1 overexpression. Here, we demonstrate that arsenic trioxide (ATO) inhibits tumor cell growth of malignant rhabdoid tumors in vitro and in a mouse xenograft model by suppressing Gli1. Our data uncover ATO as a promising therapeutic approach to improve prognosis for rhabdoid tumor patients. PMID:24420698
Kerl, Kornelius; Moreno, Natalia; Holsten, Till; Ahlfeld, Julia; Mertins, Julius; Hotfilder, Marc; Kool, Marcel; Bartelheim, Kerstin; Schleicher, Sabine; Handgretinger, Rupert; Sch�ller, Ulrich; Meisterernst, Michael; Fr�hwald, Michael C
Tumor suppressor TSLC1 inhibits growth, proliferation, invasiveness and angiogenesis in nude mice xenografted tumor of Eca109 cells
Tumor suppressor in lung cancer 1 (TSLC1) is a novel tumor suppressor gene whose inactivation is implicated in the occurrence, invasion, metastasis and prognosis of esophageal cancer. TSLC1 was studied by comparing the tumor formation of TSLC1 transfectant and control cells in nude mice. Compared with blank group and mock group, tumor size and infiltrating range of transfected group was less, differentiation of tumor tissue was slightly better, and differences of tumor angiogenesis was worse. There was no obvious difference between blank group and mock group. We have shown TSLC1 gene inhibited the growth proliferation, infiltration and angiogenesis of Eca109 cells.
Liang, Qi-Lian; Chen, Guo-Qiang; Liu, Qiu-Long; Li, Zhou-Yu; Zhang, Xiang-Ning; Zhou, Yuan; Ou, Wen-Ting; Wang, Bi-Rong; Hu, Li-Ren
Review of Growth Inhibitory Peptide as a Biotherapeutic agent for tumor growth, adhesion, and metastasis
This review surveys the biological activities of an alpha-fetoprotein (AFP) derived peptide termed the Growth Inhibitory Peptide (GIP), which is a synthetic 34 amino acid segment produced from the full length 590 amino acid AFP molecule. The GIP has been shown to be growth-suppressive in both fetal and tumor cells but not in adult terminally-differentiated cells. The mechanism of action
M. Muehlemann; K. D. Miller; M. Dauphinee; G. J. Mizejewski
Update of Alpha Fetoprotein Growth-Inhibitory Peptides as Biotherapeutic Agents for Tumor Growth and Metastasis
The present update describes the biological activities of an alpha fetoprotein (AFP)-derived peptide termed the growth-inhibitory peptide (GIP), which is a synthetic 34-amino acid segment produced from the native molecule. The GIP has been shown to be growth-suppressive in both fetal and tumor cells but not in adult cells. Even though its mechanism of action has not been completely elucidated,
G. J. Mizejewski; M. Muehlemann; M. Dauphinee
PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition
Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)alpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPARalpha would promote tumor growth. Surprisingly, the PPARalpha agonist
Dipak Panigrahy; Arja Kaipainen; Sui Huang; Catherine E. Butterfield; Carmen M. Barn�s; Michael Fannon; Andrea M. Laforme; Deviney M. Chaponis; Judah Folkman; Mark W. Kieran
Disorders of growth and puberty in children with non-tumoral hydrocephalus.
Hydrocephalus may cause disorders of growth and puberty. 31 patients (25 girls) with non-tumoral hydrocephalus were seen at 8.5 +/- 3.1 (SD) years for short stature (8 patients), overweight (8 patients), central early puberty (onset before 9 years, 21 patients), premature pubarche (1 patient) and/or delayed puberty (2 patients). Among the patients with short stature, 4 had meningomyelocele and one had untreated early puberty. Only 1/11 patients evaluated had growth hormone deficiency. Among the overweight patients, 5 had early puberty. The plasma leptin concentrations were positively correlated with the body mass index (r = 0.65, p < 0.01, n = 14). Free thyroxin, cortisol, prolactin and concomitant plasma and urinary osmolalities were normal in all cases evaluated, except one who had low free thyroxin. The 7 patients with early puberty and who were given gonadotropin releasing hormone analog for over 2 years had mean predicted adult height of -2.45 +/- 1.9 SD before treatment and -2.46 +/- 1.4 SD afterwards. Ventriculocisternostomy performed on 2 girls seen for delayed puberty was followed by breast development and menarche. In conclusion, in children with hydrocephalus, short stature is frequently due to meningomyelocele and rarely to GH deficiency. Central early puberty is the most frequent endocrine disorder. PMID:11308050
Cholley, F; Trivin, C; Sainte-Rose, C; Souberbielle, J C; Cinalli, G; Brauner, R
Nerve Growth Factor from Cobra Venom Inhibits the Growth of Ehrlich Tumor in Mice
The effects of nerve growth factor (NGF) from cobra venom (cvNGF) on growth of Ehrlich ascites carcinoma (EAC) cells inoculated subcutaneously in mice have been studied. The carcinoma growth slows down, but does not stop, during a course of cvNGF injections and restores after the course has been discontinued. The maximal anti-tumor effect has been observed at a dose of 8 nmoles cvNGF/kg body weight. cvNGF does not impact on lifespan of mice with grafted EAC cells. K252a, a tyrosine kinase inhibitor, attenuates the anti-tumor effect of cvNGF indicating the involvement of TrkA receptors in the process. cvNGF has induced also increase in body weight of the experimental animals. In overall, cvNGF shows the anti-tumor and weight-increasing effects which are opposite to those described for mammalian NGF (mNGF). However in experiments on breast cancer cell line MCF-7 cvNGF showed the same proliferative effects as mNGF and had no cytotoxic action on tumor cells in vitro. These data suggest that cvNGF slows down EAC growth via an indirect mechanism in which TrkA receptors are involved.
Osipov, Alexey V.; Terpinskaya, Tatiana I.; Kryukova, Elena V.; Ulaschik, Vladimir S.; Paulovets, Lubov V.; Petrova, Elena A.; Blagun, Ekaterina V.; Starkov, Vladislav G.; Utkin, Yuri N.
Nerve growth factor from cobra venom inhibits the growth of Ehrlich tumor in mice.
The effects of nerve growth factor (NGF) from cobra venom (cvNGF) on growth of Ehrlich ascites carcinoma (EAC) cells inoculated subcutaneously in mice have been studied. The carcinoma growth slows down, but does not stop, during a course of cvNGF injections and restores after the course has been discontinued. The maximal anti-tumor effect has been observed at a dose of 8 nmoles cvNGF/kg body weight. cvNGF does not impact on lifespan of mice with grafted EAC cells. K252a, a tyrosine kinase inhibitor, attenuates the anti-tumor effect of cvNGF indicating the involvement of TrkA receptors in the process. cvNGF has induced also increase in body weight of the experimental animals. In overall, cvNGF shows the anti-tumor and weight-increasing effects which are opposite to those described for mammalian NGF (mNGF). However in experiments on breast cancer cell line MCF-7 cvNGF showed the same proliferative effects as mNGF and had no cytotoxic action on tumor cells in vitro. These data suggest that cvNGF slows down EAC growth via an indirect mechanism in which TrkA receptors are involved. PMID:24577582
Osipov, Alexey V; Terpinskaya, Tatiana I; Kryukova, Elena V; Ulaschik, Vladimir S; Paulovets, Lubov V; Petrova, Elena A; Blagun, Ekaterina V; Starkov, Vladislav G; Utkin, Yuri N
Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells.
Exogenous ribonucleases are known to inhibit tumor growth via apoptosis induction in tumor cells, allowing to consider them as promising anticancer drugs for clinical application. In this work the antitumor potential of binase was evaluated in vivo and the mechanism of cytotoxic effect of binase on tumor cells was comprehensively studied in vitro. We investigated tumoricidal activity of binase using three murine tumor models of Lewis lung carcinoma (LLC), lymphosarcoma RLS 40 and melanoma B-16. We show for the first time that intraperitoneal injection of binase at a dose range 0.1-5 mg/kg results in retardation of primary tumor growth up to 45% in LLC and RLS 40 and inhibits metastasis up to 50% in LLC and RLS 40 and up to 70% in B-16 melanoma. Binase does not exhibit overall toxic effect and displays a general systemic and immunomodulatory effects. Treatment of RLS 40-bearing animals with binase together with polychemotherapy revealed that binase decreases the hepatotoxicity of polychemotherapy while maintaining its antitumor effect. It was demonstrated that the cytotoxic effect of binase is realized via the induction of the intrinsic and extrinsic apoptotic pathways. Activation of intrinsic apoptotic pathway is manifested by a drop of mitochondrial potential, increase in calcium concentration and inhibition of respiratory activity. Subsequent synthesis of TNF-? in the cells under the action of binase triggers extrinsic apoptotic pathway through the binding of TNF with cell-death receptors and activation of caspase 8. Thus binase is a potential anticancer therapeutics inducing apoptosis in cancer cells. PMID:23759588
Mironova, Nadezhda L; Petrushanko, Irina Y; Patutina, Olga A; Sen'kova, Aexandra V; Simonenko, Olga V; Mitkevich, Vladimir A; Markov, Oleg V; Zenkova, Marina A; Makarov, Alexander A
Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells
Exogenous ribonucleases are known to inhibit tumor growth via apoptosis induction in tumor cells, allowing to consider them as promising anticancer drugs for clinical application. In this work the antitumor potential of binase was evaluated in vivo and the mechanism of cytotoxic effect of binase on tumor cells was comprehensively studied in vitro. We investigated tumoricidal activity of binase using three murine tumor models of Lewis lung carcinoma (LLC), lymphosarcoma RLS40 and melanoma B-16. We show for the first time that intraperitoneal injection of binase at a dose range 0.1�5 mg/kg results in retardation of primary tumor growth up to 45% in LLC and RLS40 and inhibits metastasis up to 50% in LLC and RLS40 and up to 70% in B-16 melanoma. Binase does not exhibit overall toxic effect and displays a general systemic and immunomodulatory effects. Treatment of RLS40-bearing animals with binase together with polychemotherapy revealed that binase decreases the hepatotoxicity of polychemotherapy while maintaining its antitumor effect. It was demonstrated that the cytotoxic effect of binase is realized via the induction of the intrinsic and extrinsic apoptotic pathways. Activation of intrinsic apoptotic pathway is manifested by a drop of mitochondrial potential, increase in calcium concentration and inhibition of respiratory activity. Subsequent synthesis of TNF-? in the cells under the action of binase triggers extrinsic apoptotic pathway through the binding of TNF with cell-death receptors and activation of caspase 8. Thus binase is a potential anticancer therapeutics inducing apoptosis in cancer cells.
Mironova, Nadezhda L.; Petrushanko, Irina Y.; Patutina, Olga A.; Sen'kova, Aexandra V.; Simonenko, Olga V.; Mitkevich, Vladimir A.; Markov, Oleg V.; Zenkova, Marina A.; Makarov, Alexander A.
Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells
Epidermal growth factor receptor (EGFR) targeting agents such as kinase inhibitors reduce tumor growth and progression. We have previously reported that EGFR is not only expressed by the tumor cells but by the tumor endothelial cells (EC) as well (Amin, D. N., Hida, K., Bielenberg, D. R., Klagsbrun, M., 2006. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but
Dhara N. Amin; Diane R. Bielenberg; Eugene Lifshits; John V. Heymach; Michael Klagsbrun
Newer concepts of cancer of the colon and rectum: Delayed hypersensitivity responses of patients with carcinoma of the colon and other solid tumors
Summary��Eighty-nine patients were skin-tested with four delayed allergens: old tuberculin, mumps, streptokinase-streptodornase, andTrichophyton. Forty-eight of these patients, including 43 with carcinoma of the colon, had nonreticuloendothelial tumors. Patients with\\u000a tumors were otherwise in good health. There were significant differences between the delayed skin sensitivity of patients\\u000a with cancer and those without cancer, and between the responses to challenge with streptokinase-streptodornase
Barry S. Kronman; Howard M. Shapiro; S. Arthur Locallo
The Motor Protein KIF14 Inhibits Tumor Growth and Cancer Metastasis in Lung Adenocarcinoma
The motor protein kinesin superfamily proteins (KIFs) are involved in cancer progression. The depletion of one of the KIFs, KIF14, might delay the metaphase-to-anaphase transition, resulting in a binucleated status, which enhances tumor progression; however, the exact correlation between KIF14 and cancer progression remains ambiguous. In this study, using loss of heterozygosity and array comparative genomic hybridization analyses, we observed a 30% loss in the regions surrounding KIF14 on chromosome 1q in lung adenocarcinomas. In addition, the protein expression levels of KIF14 in 122 lung adenocarcinomas also indicated that approximately 30% of adenocarcinomas showed KIF14 down-regulation compared with the expression in the bronchial epithelial cells of adjacent normal counterparts. In addition, the reduced expression of KIF14 mRNA or proteins was correlated with poor overall survival (P?=?0.0158 and <0.0001, respectively), and the protein levels were also inversely correlated with metastasis (P<0.0001). The overexpression of KIF14 in lung adenocarcinoma cells inhibited anchorage-independent growth in vitro and xenograft tumor growth in vivo. The overexpression and silencing of KIF14 also inhibited or enhanced cancer cell migration, invasion and adhesion to the extracellular matrix proteins laminin and collagen IV. Furthermore, we detected the adhesion molecules cadherin 11 (CDH11) and melanoma cell adhesion molecule (MCAM) as cargo on KIF14. The overexpression and silencing of KIF14 enhanced or reduced the recruitment of CDH11 in the membrane fraction, suggesting that KIF14 might act through recruiting adhesion molecules to the cell membrane and modulating cell adhesive, migratory and invasive properties. Thus, KIF14 might inhibit tumor growth and cancer metastasis in lung adenocarcinomas.
Hung, Pei-Fang; Hong, Tse-Ming; Hsu, Yi-Chiung; Chen, Hsuan-Yu; Chang, Yih-Leong; Wu, Chen-Tu; Chang, Gee-Chen; Jou, Yuh-Shan
Tubulin binding cofactor C (TBCC) suppresses tumor growth and enhances chemosensitivity in human breast cancer cells
Background Microtubules are considered major therapeutic targets in patients with breast cancer. In spite of their essential role in biological functions including cell motility, cell division and intracellular transport, microtubules have not yet been considered as critical actors influencing tumor cell aggressivity. To evaluate the impact of microtubule mass and dynamics on the phenotype and sensitivity of breast cancer cells, we have targeted tubulin binding cofactor C (TBCC), a crucial protein for the proper folding of ? and ? tubulins into polymerization-competent tubulin heterodimers. Methods We developed variants of human breast cancer cells with increased content of TBCC. Analysis of proliferation, cell cycle distribution and mitotic durations were assayed to investigate the influence of TBCC on the cell phenotype. In vivo growth of tumors was monitored in mice xenografted with breast cancer cells. The microtubule dynamics and the different fractions of tubulins were studied by time-lapse microscopy and lysate fractionation, respectively. In vitro sensitivity to antimicrotubule agents was studied by flow cytometry. In vivo chemosensitivity was assayed by treatment of mice implanted with tumor cells. Results TBCC overexpression influenced tubulin fraction distribution, with higher content of nonpolymerizable tubulins and lower content of polymerizable dimers and microtubules. Microtubule dynamicity was reduced in cells overexpressing TBCC. Cell cycle distribution was altered in cells containing larger amounts of TBCC with higher percentage of cells in G2-M phase and lower percentage in S-phase, along with slower passage into mitosis. While increased content of TBCC had little effect on cell proliferation in vitro, we observed a significant delay in tumor growth with respect to controls when TBCC overexpressing cells were implanted as xenografts in vivo. TBCC overexpressing variants displayed enhanced sensitivity to antimicrotubule agents both in vitro and in xenografts. Conclusion These results underline the essential role of fine tuned regulation of tubulin content in tumor cells and the major impact of dysregulation of tubulin dimer content on tumor cell phenotype and response to chemotherapy. A better understanding of how the microtubule cytoskeleton is dysregulated in cancer cells would greatly contribute to a better understanding of tumor cell biology and characterisation of resistant phenotypes.
Identification of Sonic Hedgehog-Induced Stromal Factors That Stimulate Prostate Tumor Growth.
National Technical Information Service (NTIS)
We will determine the mechanism by which Shh signaling accelerates prostate tumor growth, identify Shh targets in prostate tumor stroma, and test the effect of individual target genes on tumor growth. The purpose of the report is to evaluate the first yea...
A. Shaw W. Bushman
Overexpression of factor inhibiting HIF-1 enhances vessel maturation and tumor growth via platelet-derived growth factor-C.
Recent studies have revealed that the maturation state of vessels in tumors, in addition to vascularity, is a critical determinant of tumor growth. The role of oxygen-dependent signaling pathways in hypoxia-stimulated angiogenesis is well established, however, little is known about their impact on vessel maturation in tumors. Here, we have studied the function of the cellular oxygen sensor, factor inhibiting HIF-1 (FIH), which controls the activity of hypoxia-inducible factor-1. FIH silencing in mouse LM8 osteosarcoma stimulated angiogenesis but did not influence tumor growth. In contrast, FIH overexpression led to increased pericyte coverage of the tumor vasculature, reduced vessel leakiness and enhanced tumor growth. Vessel maturation was paralleled by up-regulation of platelet-derived growth factor (PDGF)-C in tumors and expression of PDGF receptor-? on pericytes. Ablation of PDGF-C in FIH-overexpressing tumor cells reduced pericyte coverage and tumor growth. Our data suggest that FIH-mediated PDGF-C induction in LM8 osteosarcoma stimulates the recruitment of PDGFR-? positive pericytes to the tumor vasculature, leading to vessel maturation and enhanced tumor growth. PMID:22095574
Kuzmanov, Aleksandar; Wielockx, Ben; Rezaei, Maryam; Kettelhake, Antje; Breier, Georg
In vivo imaging-based mathematical modeling techniques that enhance the understanding of oncogene addiction in relation to tumor growth.
The dependence on the overexpression of a single oncogene constitutes an exploitable weakness for molecular targeted therapy. These drugs can produce dramatic tumor regression by targeting the driving oncogene, but relapse often follows. Understanding the complex interactions of the tumor's multifaceted response to oncogene inactivation is key to tumor regression. It has become clear that a collection of cellular responses lead to regression and that immune-mediated steps are vital to preventing relapse. Our integrative mathematical model includes a variety of cellular response mechanisms of tumors to oncogene inactivation. It allows for correct predictions of the time course of events following oncogene inactivation and their impact on tumor burden. A number of aspects of our mathematical model have proven to be necessary for recapitulating our experimental results. These include a number of heterogeneous tumor cell states since cells following different cellular programs have vastly different fates. Stochastic transitions between these states are necessary to capture the effect of escape from oncogene addiction (i.e., resistance). Finally, delay differential equations were used to accurately model the tumor growth kinetics that we have observed. We use this to model oncogene addiction in MYC-induced lymphoma, osteosarcoma, and hepatocellular carcinoma. PMID:23573174
Nwabugwu, Chinyere; Rakhra, Kavya; Felsher, Dean; Paik, David
In Vivo Imaging-Based Mathematical Modeling Techniques That Enhance the Understanding of Oncogene Addiction in relation to Tumor Growth
The dependence on the overexpression of a single oncogene constitutes an exploitable weakness for molecular targeted therapy. These drugs can produce dramatic tumor regression by targeting the driving oncogene, but relapse often follows. Understanding the complex interactions of the tumor's multifaceted response to oncogene inactivation is key to tumor regression. It has become clear that a collection of cellular responses lead to regression and that immune-mediated steps are vital to preventing relapse. Our integrative mathematical model includes a variety of cellular response mechanisms of tumors to oncogene inactivation. It allows for correct predictions of the time course of events following oncogene inactivation and their impact on tumor burden. A number of aspects of our mathematical model have proven to be necessary for recapitulating our experimental results. These include a number of heterogeneous tumor cell states since cells following different cellular programs have vastly different fates. Stochastic transitions between these states are necessary to capture the effect of escape from oncogene addiction (i.e., resistance). Finally, delay differential equations were used to accurately model the tumor growth kinetics that we have observed. We use this to model oncogene addiction in MYC-induced lymphoma, osteosarcoma, and hepatocellular carcinoma.
Nwabugwu, Chinyere; Rakhra, Kavya; Felsher, Dean
Notch1 and Notch2 Have Opposite Effects on Embryonal Brain Tumor Growth
The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell
Xing Fan; Irina Mikolaenko; Ihab Elhassan; XingZhi Ni; Yunyue Wang; Douglas Ball; Daniel J. Brat; Arie Perry; Charles G. Eberhart
Tumor-host interaction: Analysis of cytokines, growth factors, and tumorinfiltrating lymphocytes in ovarian carcinomas
The host-tumor interaction may play an important role in determining tumor progress. Recent studies have shown that this interaction can be influenced by the release of soluble factors by tumor cells and tumor-infiltrating lymphocytes (TIL). The aim of our study is to characterize the nature of cytokines and growth factors and their relationship to the cellular infiltrates in 16 patients
Athir J Merogi; Aizen J Marrogi; Rajagopal Ramesh; William R Robinson; Cesar D Fermin; Scott M Freeman
Preferential Sites of Growth of Human Tumors in Nude Mice following Subcutaneous Transplantation1
The growth characteristics and biological behavior of human tumors transplanted s.c. into two different anatomical regions of nude mice were studied. It was observed that tumors trans planted in the anterior lateral thoracic wall grew faster than did tumors transplanted in the posterior aspect of the trunk. Ante riorly growing tumors, in contrast to the posteriorly transplanted ones, were better
Aikaterini A. Kyriazis; Andreas P. Kyriazis
Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis
Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneficial effects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These effects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Specific signal transduction cascades that emanate from different nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor effects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent efforts to target the nicotinic acetylcholine receptors to combat cancer.
Singh, Sandeep; Pillai, Smitha; Chellappan, Srikumar
Human choriocarcinomas: placental growth factor-dependent preclinical tumor models.
Choriocarcinomas are a rare form of cancer that develops in the uterus from tissue which would normally become the placenta. Choriocarcinomas are a trophoblastic gestational disease and have been studied largely to investigate conditions related to pregnancy such as preeclampsia. Choriocarcinomas are highly angiogenic and produce high levels of placental growth factor (PlGF) to promote the development of blood vessels. Upregulation of PlGF expression also occurs during the development of other human malignancies such as breast cancer and melanoma. Both tumor specimens and plasma samples have higher levels of PlGF than normal tissues. Hence, PlGF has emerged as a valid target for anti-angiogenic therapy. The cell lines BeWo, JAR and JEG-3, derived from human choriocarcinomas, were investigated in vitro and in vivo for suitability as PlGF-dependent models. BeWo, JAR and JEG-3 cells were characterized in culture and were implanted into immunodeficient mice to generate subcutaneous tumors. The PlGF and VEGF angiogenic profiles of the choriocarcinoma cells and tumors were investigated by ELISA and by immunohistochemical methods. Double immunofluorescence methods were applied to choriocarcinoma xenograft sections to characterize the cellular components of the blood vessels. sFLT01, a fusion protein that neutralizes PlGF, was assessed in cell culture experiments and xenograft studies. The novel results presented here validate the importance of human choriocarcinoma cell lines and xenografts in further exploring the role of PlGF in tumor angiogenesis, for evaluating PlGF as an anti-angiogenic target, and for developing therapies that may provide clinical benefit. PMID:22075622
Bagley, Rebecca G; Ren, Yi; Kurtzberg, Leslie; Weber, William; Bangari, Dinesh; Brondyk, William; Teicher, Beverly A
Macrophage Migration Inhibitory Factor promotes tumor growth and metastasis by inducing Myeloid Derived Suppressor Cells in the tumor microenvironment
The Macrophage Migration Inhibitory Factor (MIF), an inflammatory cytokine, is overexpressed in many solid tumors and is associated with poor prognosis. We previously identified inhibitors of MIF within a class of natural products with demonstrated anti-cancer activities. We therefore sought to determine how MIF contributes to tumor growth and progression. We show here that, in murine tumors including the 4T1 model of aggressive, spontaneously metastatic breast cancer in immunologically intact mice, tumor-derived MIF promotes tumor growth and pulmonary metastasis through control of inflammatory cells within the tumor. Specifically, MIF increases the prevalence of a highly immune suppressive subpopulation of myeloid derived suppressor cells (MDSCs) within the tumor. In vitro, MIF promotes differentiation of myeloid cells into the same population of MDSCs. Pharmacologic inhibition of MIF reduces MDSC accumulation in the tumor similar to MIF depletion, and blocks the MIF-dependent in vitro differentiation of MDSCs. Our results demonstrate that MIF is a therapeutically targetable mechanism for control of tumor growth and metastasis through regulation of the host immune response, and support the potential utility of MIF inhibitors, either alone or in combination with standard tumor-targeting therapeutic or immunotherapy approaches.
Simpson, Kendra D.; Templeton, Dennis J.; Cross, Janet V.
Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model
This study evaluated a biodegradable drug delivery system for local cancer radiotherapy consisting of a thermally sensitive elastin-like polypeptide (ELP) conjugated to a therapeutic radionuclide. Two ELPs (49 kD) were synthesized using genetic engineering to test the hypothesis that injectable biopolymeric depots can retain radionuclides locally and reduce the growth of tumors. A thermally sensitive polypeptide, ELP1, was designed to spontaneously undergo a soluble-insoluble phase transition (forming viscous microparticles) between room temperature and body temperature upon intratumoral injection, while ELP2 was designed to remain soluble upon injection and to serve as a negative control for the effect of aggregate assembly. After intratumoral administration of radionuclide conjugates of ELPs into implanted tumor xenografts in nude mice, their retention within the tumor, spatio-temporal distribution, and therapeutic effect were quantified. The residence time of the radionuclide-ELP1 in the tumor was significantly longer than the thermally insensitive ELP2 conjugate. In addition, the thermal transition of ELP1 significantly protected the conjugated radionuclide from dehalogenation, whereas the conjugated radionuclide on ELP2 was quickly eliminated from the tumor and cleaved from the biopolymer. These attributes of the thermally sensitive ELP1 depot improved the antitumor efficacy of iodine-131 compared to the soluble ELP2 control. This novel injectable and biodegradable depot has the potential to control advanced-stage cancers by reducing the bulk of inoperable tumors, enabling surgical removal of de-bulked tumors, and preserving healthy tissues.
Liu, Wenge; MacKay, J. Andrew; Dreher, Matthew R.; Chen, Mingnan; McDaniel, Jonathan R.; Simnick, Andrew J.; Callahan, Daniel J.; Zalutsky, Michael R.; Chilkoti, Ashutosh
T model of growth and its application in systems of tumor-immune dynamics.
In this paper we introduce a new growth model called T growth model. This model is capable of representing sigmoidal growth as well as biphasic growth. This dual capability is achieved without introducing additional parameters. The T model is useful in modeling cellular proliferation or regression of cancer cells, stem cells, bacterial growth and drug dose-response relationships. We recommend usage of the T growth model for the growth of tumors as part of any system of differential equations. Use of this model within a system will allow more flexibility in representing the natural rate of tumor growth. For illustration, we examine some systems of tumor-immune interaction in which the T growth rate is applied. We also apply the model to a set of tumor growth data. PMID:23906156
Tabatabai, Mohammad A; Eby, Wayne M; Singh, Karan P; Bae, Sejong
Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors
Angiogenesis is required for the progres- sion of tumors from a benign to a malig- nant phenotype and for metastasis. Malig- nant tumor cells secrete factors such as vascular endothelial growth factor (VEGF), which bind to their cognate receptors on endothelial cells to induce angiogenesis. Here it is shown that several tumor types express VEGF receptors (VEGFRs) and that inhibition
Rizwan Masood; Jie Cai; Tong Zheng; D. Lynne Smith; David R. Hinton; Parkash S. Gill
Extracellular Matrix Metalloproteinase Inducer Stimulates Tumor Angiogenesis by Elevating Vascular Endothelial Cell Growth Factor and Matrix Metalloproteinases
Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell-associated extracellular matrix metalloproteinase in- ducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN
Yi Tang; Marian T. Nakada; Prabakaran Kesavan; Francis McCabe; Hillary Millar; Patricia Rafferty; Peter Bugelski
Reexpression of LSAMP inhibits tumor growth in a preclinical osteosarcoma model
Background Osteosarcomas are the most common primary malignant tumors of bone, showing complex chromosomal rearrangements with multiple gains and losses. A frequent deletion within the chromosomal region 3q13.31 has been identified by us and others, and is mainly reported to be present in osteosarcomas. The purpose of the study was to further characterize the frequency and the extent of the deletion in an extended panel of osteosarcoma samples, and the expression level of the affected genes within the region. We have identified LSAMP as the target gene for the deletion, and have studied the functional implications of LSAMP-reexpression. Methods LSAMP copy number, expression level and protein level were investigated by quantitative PCR and western blotting in an osteosarcoma panel. The expression of LSAMP was restored in an osteosarcoma cell line, and differences in proliferation rate, tumor formation, gene expression, migration rate, differentiation capabilities, cell cycle distribution and apoptosis were investigated by metabolic dyes, tumor formation in vivo, gene expression profiling, time-lapse photography, differentiation techniques and flow cytometry, respectively. Results We found reduced copy number of LSAMP in 45/76 osteosarcoma samples, reduced expression level in 25/42 samples and protein expression in 9/42 samples. By restoring the expression of LSAMP in a cell line with a homozygous deletion of the gene, the proliferation rate in vitro was significantly reduced and tumor growth in vivo was significantly delayed. In response to reexpression of LSAMP, mRNA expression profiling revealed consistent upregulation of the genes hairy and enhancer of split 1 (HES1), cancer/testis antigen 2 (CTAG2) and kruppel-like factor 10 (KLF10). Conclusions The high frequency and the specificity of the deletion indicate that it is important for the development of osteosarcomas. The deletion targets the tumor suppressor LSAMP, and based on the functional evidence, the tumor suppressor function of LSAMP is most likely exerted by reducing the proliferation rate of the tumor cells, possibly by indirectly upregulating one or more of the genes HES1, CTAG2 or KLF10. To our knowledge, this study describes novel functions of LSAMP, a first step to understanding the functional role of this specific deletion in osteosarcomas.
Bone cancer pain: the effects of the bisphosphonate alendronate on pain, skeletal remodeling, tumor growth and tumor necrosis
Patients with metastatic breast, lung or prostate cancer frequently have significant bone cancer pain. In the present report we address, in a single in vivo mouse model, the effects the bisphosphonate alendronate has on bone cancer pain, bone remodeling and tumor growth and necrosis. Following injection and confinement of green fluorescent protein-transfected murine osteolytic tumor cells into the marrow space
Molly A. Sevcik; Nancy M. Luger; David B. Mach; Mary Ann C. Sabino; Christopher M. Peters; Joseph R. Ghilardi; Matthew J. Schwei; Heidi R�hrich; Carmen De Felipe; Michael A. Kuskowski; Patrick W. Mantyh
Expression of the Type-1 Repeats of Thrombospondin-1 Inhibits Tumor Growth Through Activation of Transforming Growth Factor-?
In the present study, the type-1 repeats of thrombospondin-1 (TSP-1) were transfected into A431 cells. Expression of all three type-1 repeats (3TSR) and expression of just the second type-1 repeat containing the transforming growth factor (TGF)-? activating sequence KRFK (TSR2 + KRFK) significantly inhibited in vivo tumor angiogenesis and growth in nude mice. These tumors expressed increased levels of both active and total TGF-?. A431 cells expressing the second type-1 repeat without the KRFK sequence (TSR2 ? KRFK) produced tumors that were slightly larger than the 3TSR and TSR2 + KRFK tumors. These tumors expressed elevated levels of active TGF-? but levels of total TGF-? were not different from control tumors. Injection of the peptide, LSKL, which blocks TSP-1 activation of TGF-?, reversed the growth inhibition observed with cells expressing TSR2 + KRFK to a level comparable to controls. Various residues in the WSHWSPW region and the VTCG sequence of both TSR2+/? KRFK were mutated. Although mutation of the VTCG sequence had no significant effect on tumor growth, mutation of the WSHWSPW sequence reduced inhibition of tumor growth. These findings suggest that the inhibition of tumor angiogenesis and growth by endogenous TSP-1 involves regulation of both active and total TGF-? and the sequences KRFK and WSHWSPW in the second type-1 repeat.
Yee, Karen O.; Streit, Michael; Hawighorst, Thomas; Detmar, Michael; Lawler, Jack
The effect of surgery and pretreatment or posttreatment adjuvant chemotherapy on primary tumor growth in an animal model.
The Ca755 solid tumor in the C57B1 mouse has been used as a model to study the interrelationship of surgery and adjuvant chemotherapy on primary tumor growth. Surgery was performed on various days after tumor implantation. Surgical mortality increased with delay in surgery. The mean survival time (MST) was significantly increased by surgery. An increased cure rate in mice with late surgery may be due to immunological factors. Pretreatment cytoxan chemotherapy prior to a number of surgical days on the most effect schedule increased MST in the later surgical days primarily due to shrinkage of tumor and a diminished surgical mortality. Posttreatment chemotherapy significantly increased MST primarily on the basis of reducing tumor cell population after surgery and increasing both the cure rate and the time until death of those mice dying of regrowth of tumor. Optimal chemotherapy alone significantly increased MST compared to untreated controls. Optimal postsurgery chemotherapy increased survival longer than the additive increase of chemotherapy alone and surgery alone. This paper illustrates relationships between day of surgery dose and schedule of chemotherapy and effect on various measurable parameters. The results can best be understood in relationship to each other. It is suggested that adjuvant chemotherapy has specific definable benefits. It is apparent from human studies that carefully devised designs which consider these interrelationships are necessary if optimal therapeutic results are to be achieved. PMID:1186267
Straus, M J; Sege, V; Choi, S C
Perfluorochemical emulsions can increase tumor radiosensitivity
An oxygen-carrying perfluorochemical emulsion enhanced the effectiveness of radiation therapy in two transplantable solid tumors in mice. The perfluorochemical emulsion had no effect on tumor growth after x-irradiation, but delayed tumor growth significantly when administered to oxygen-breathing mice before or during irradiation.
B. A. Teicher; C. M. Rose
Targeting Gli transcription activation by small molecule suppresses tumor growth.
Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy. PMID:23686308
Bosco-Cl�ment, G; Zhang, F; Chen, Z; Zhou, H-M; Li, H; Mikami, I; Hirata, T; Yagui-Beltran, A; Lui, N; Do, H T; Cheng, T; Tseng, H-H; Choi, H; Fang, L-T; Kim, I-J; Yue, D; Wang, C; Zheng, Q; Fujii, N; Mann, M; Jablons, D M; He, B
Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth.
One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion. PMID:24121491
Wegiel, Barbara; Gallo, David; Csizmadia, Eva; Harris, Clair; Belcher, John; Vercellotti, Gregory M; Penacho, Nuno; Seth, Pankaj; Sukhatme, Vikas; Ahmed, Asif; Pandolfi, Pier Paolo; Helczynski, Leszek; Bjartell, Anders; Persson, Jenny Liao; Otterbein, Leo E
Phosphocaveolin-1 Enforces Tumor Growth and Chemoresistance in Rhabdomyosarcoma
Caveolin-1 (Cav-1) can ambiguously behave as either tumor suppressor or oncogene depending on its phosphorylation state and the type of cancer. In this study we show that Cav-1 was phosphorylated on tyrosine 14 (pCav-1) by Src-kinase family members in various human cell lines and primary mouse cultures of rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma affecting childhood. Cav-1 overexpression in the human embryonal RD or alveolar RH30 cells yielded increased pCav-1 levels and reinforced the phosphorylation state of either ERK or AKT kinase, respectively, in turn enhancing in vitro cell proliferation, migration, invasiveness and chemoresistance. In contrast, reducing the pCav-1 levels by administration of a Src-kinase inhibitor or through targeted Cav-1 silencing counteracted the malignant in vitro phenotype of RMS cells. Consistent with these results, xenotransplantation of Cav-1 overexpressing RD cells into nude mice resulted in substantial tumor growth in comparison to control cells. Taken together, these data point to pCav-1 as an important and therapeutically valuable target for overcoming the progression and multidrug resistance of RMS.
Faggi, Fiorella; Mitola, Stefania; Sorci, Guglielmo; Riuzzi, Francesca; Donato, Rosario; Codenotti, Silvia; Poliani, Pietro Luigi; Cominelli, Manuela; Vescovi, Raffaella; Rossi, Stefania; Calza, Stefano; Colombi, Marina; Penna, Fabio; Costelli, Paola; Perini, Ilaria; Sampaolesi, Maurilio; Monti, Eugenio; Fanzani, Alessandro
Slit2 promotes tumor growth and invasion in chemically induced skin carcinogenesis.
Slit, a neuronal guidance cue, binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit has been reported to have an important effect on tumor growth and metastasis. In the current study, we evaluated the role of Slit2 in skin tumor growth and invasion in mice using a two-step chemical carcinogenesis protocol. We found that Slit2 expression correlated with the loss of basement membrane in the samples of human skin squamous cell carcinoma at different stages of disease progression. Slit2-Tg mice developed significantly more skin tumors than wild-type mice. Furthermore, the skin tumors that occurred in Slit2-Tg mice were significantly larger than those in the wild-type mice 10 weeks after 7,12-dimethylbenz[a]anthracene initiation until the end of the experiment. We also found that pathological development of the wild-type mice was delayed compared with that of Slit2-Tg mice. To further investigate the mechanism of increasing tumors in Slit2-Tg mice, we analyzed the expression of 5-bromo-2'-deoxyuridine (BrdU) in mouse skin lesions and found that the number of BrdU-positive cells and microvessel density in skin lesions were significantly higher in Slit2-Tg mice than in wild-type mice. Histological staining of PAS and type IV collagen and the colocalization of Slit2 and type IV collagen demonstrated varying degrees of loss of the basement membrane in the skin lesions from Slit2-Tg mice that were at the stage of carcinoma in situ. However, the basement membrane was well defined in the wild-type mice. In addition, MMP2, but not MMP9, was upregulated in the skin tissue of Slit2-Tg mice. Interruption of Slit2-Robo1 signaling by the antibody R5 significantly repressed the invasive capability of the squamous cell carcinoma cell line A431. Taken together, our findings reveal that Slit2 promotes DMBA/TPA-induced skin tumorigenesis by increasing cell proliferation, microvessel density, and invasive behavior of cutaneous squamous cell carcinoma, along with loss of basement membrane, by upregulation of MMP2 expression. PMID:24840330
Qi, Cuiling; Lan, Haimei; Ye, Jie; Li, Weidong; Wei, Ping; Yang, Yang; Guo, Simei; Lan, Tian; Li, Jiangchao; Zhang, Qianqian; He, Xiaodong; Wang, Lijing
Antisense oligonucleotides directed against insulin-like growth factor-II messenger ribonucleic acids delay the progress of rat hepatocarcinogenesis
Background: Hepatocellular carcinoma (HCC) is a multistep complex process, caused by many of genetic alteration. Insulin-like growth factors and their receptor have been widely implicated to HCC. Insulin-like growth factor-II (IGF-II) is a mitogenic polypeptide, found in various fetal and neonatal tissues of humans and rats and expresses in HCC. Here we investigated anticancer potential of phosphorothioate antisense oligonucleotides (ASOs) against three coding exons (exon-1/exon-2/exon-3) of IGF-II messenger ribonucleic acid in rat hepatocarcinogenesis model. Materials and Methods: During diethylnitrosamine and 2-acetylaminofluorene induced hepatocarcinogenesis, rats were treated with ASOs. Various biochemical and histological studies were conducted. Results: About 40% of carcinogen treated rats, which received two oligomers (against exon-1 or-3) did not show any hepatic lesion, hyperplastic nodule or tumor and remaining 60% of those rats showed lesion incidence and had about 59% and 55% reductions in the numbers of hepatic altered foci, respectively. Reductions in the total lesion-area when compared with carcinogen control rats were 64% and 53%, respectively for the animals treated with carcinogen and received the ASOs against exon-1/-3. Fluorescein isothiocyanate-labeled ASO reached in the hepatocytes in 2 h. No predominant IGF-II overexpression was observed in case of rats treated with the two ASOs. Treatment of the antisense IGF-II oligomers in carcinogen treated rats show better hepatocellular integrity along with several preneoplastic/neoplastic marker isoenzyme/enzyme modulations. Conclusions: Two of the three antisense oligomer-types effectively controlled IGF-II overexpression, causing the delay of the development and/or progress of hepatic cancer in rats.
Ghosh, Miltu Kumar; Patra, Falguni; Ghosh, Shampa; Hossain, Chowdhury Mobaswar; Mukherjee, Biswajit
Breast cancer is one of the most common malignancies in human females in the world. One protein that has elevated enzymatic lipase activity in breast cancers in vitro is phospholipase D (PLD), which is also involved in cell migration. We demonstrate that the PLD2 isoform, which was analyzed directly in the tumors, is crucial for cell invasion that contributes critically to the growth and development of breast tumors and lung metastases in vivo. We used three complementary strategies in a SCID mouse model and also addressed the underlying molecular mechanism. First, the PLD2 gene was silenced in highly metastatic, aggressive breast cancer cells (MDA-MB-231) with lentivirus-based shRNA, which were xenotransplanted in SCID mice. The resulting mouse primary mammary tumors were reduced in size (65%, p<0.05) and their onset delayed when compared to control tumors. Second, we stably overexpressed PLD2 in low-invasive breast cancer cells (MCF-7) with a biscistronic MIEG retroviral vector and observed that these cells were converted into a highly aggressive phenotype, as primary tumors that formed following xenotransplantation were larger, grew faster and developed lung metastases more readily. Third, we implanted osmotic pumps into SCID xenotransplanted mice that delivered two different small-molecule inhibitors of PLD activity (FIPI and NOPT). These inhibitors led to significant (>70%, p<0.05) inhibition of primary tumor growth, metastatic axillary tumors and lung metastases. In order to define the underlying mechanism, we determined that the machinery of PLD-induced cell invasion is mediated by phosphatidic acid (PA), WASp, Grb2 and Rac2 signaling events that ultimately affect actin polymerization and cell invasion. In summary, this study shows that PLD has a central role in the development, metastasis and level of aggressiveness of breast cancer, raising the possibility that PLD2 could be used as a new therapeutic target.
Henkels, Karen M.; Boivin, Gregory P.; Dudley, Emily S.; Berberich, Steven J.; Gomez-Cambronero, Julian
Basic Fibroblast Growth Factor for Treatment of Onychomadesis with Delayed Regrowth of the Nail
Onychomadesis usually arises from an inflammation of the paronychium or as a result of blisters and hemorrhaging under a nail that has been struck or compressed. No documented interactions between basic fibroblast growth factor (bFGF) and onychomadesis have hitherto been reported. This case report describes a 25-year-old woman with onychomadesis following infection of the ingrown nail of her left thumb. After ten months of observation with no treatment showed no regrowth of her left thumbnail, the external use of bFGF and antibiotic ointment was started. One month later, nail regrowth was observed up to the halfway point of the nail bed, and after treatment for three months, the regrown nail reached the top of the nail bed. Both thumbnails now looked identical. This case suggests that external use of bFGF can promote nail regrowth in cases of onychomadesis with delayed regrowth of the nail.
Oji, Tomito; Yazawa, Masaki; Kishi, Kazuo
Inhibition of endogenous reverse transcriptase antagonizes human tumor growth.
Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to inhibit RT activity in melanoma and prostate carcinoma cell lines: pharmacological inhibition by two characterized RT inhibitors, nevirapine and efavirenz, and downregulation of expression of RT-encoding LINE-1 elements by RNA interference (RNAi). Both treatments reduced proliferation, induced morphological differentiation and reprogrammed gene expression. These features are reversible upon discontinuation of the anti-RT treatment, suggesting that RT contributes to an epigenetic level of control. Most importantly, inhibition of RT activity in vivo antagonized tumor growth in animal experiments. Moreover, pretreatment with RT inhibitors attenuated the tumorigenic phenotype of prostate carcinoma cells inoculated in nude mice. Based on these data, the endogenous RT can be regarded as an epigenetic regulator of cell differentiation and proliferation and may represent a novel target in cancer therapy. PMID:15806170
Sciamanna, Ilaria; Landriscina, Matteo; Pittoggi, Carmine; Quirino, Michela; Mearelli, Cristina; Beraldi, Rosanna; Mattei, Elisabetta; Serafino, Annalucia; Cassano, Alessandra; Sinibaldi-Vallebona, Paola; Garaci, Enrico; Barone, Carlo; Spadafora, Corrado
Injectable intratumoral depot of thermally responsive polypeptide�radionuclide conjugates delays tumor progression in a mouse model
This study evaluated a biodegradable drug delivery system for local cancer radiotherapy consisting of a thermally sensitive elastin-like polypeptide (ELP) conjugated to a therapeutic radionuclide. Two ELPs (49kDa) were synthesized using genetic engineering to test the hypothesis that injectable biopolymeric depots can retain radionuclides locally and reduce the growth of tumors. A thermally sensitive polypeptide, ELP1, was designed to spontaneously
Wenge Liu; J. Andrew MacKay; Matthew R. Dreher; Mingnan Chen; Jonathan R. McDaniel; Andrew J. Simnick; Daniel J. Callahan; Michael R. Zalutsky; Ashutosh Chilkoti
Decorin suppresses tumor cell growth by activating the epidermal growth factor receptor.
Decorin, a small leucine-rich proteoglycan, is capable of suppressing the growth of various tumor cell lines when expressed ectopically. In this report, we investigated the biochemical mechanism by which decorin inhibits cell cycle progression. In A431 squamous carcinoma cells, decorin proteoglycan or protein core induced a marked growth suppression, when either exogenously added or endogenously produced by a transgene. Decorin caused rapid phosphorylation of the EGF receptor and a concurrent activation of mitogen-activated protein (MAP) kinase signal pathway. This led to a protracted induction of endogenous p21, a potent inhibitor of cyclin-dependent kinases, and ultimate cell cycle arrest. Biglycan, a related proteoglycan, had no effect. Moreover, decorin activated the EGF receptor/MAP kinase/ p21 axis in cell lines of various histogenetic backgrounds. These results provide the first evidence that EGF and decorin converge functionally to regulate the cell cycle through activation of a common pathway which ultimately leads to growth suppression.
Moscatello, D K; Santra, M; Mann, D M; McQuillan, D J; Wong, A J; Iozzo, R V
Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations.
KRAS mutations are frequent in colorectal cancer (CRC) and are associated with clinical resistance to treatment with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway and mediates stem cell self-renewal and vascular development. DLL4 inhibition in colon tumor cells reduces tumor growth and stem cell frequency. Considering the need for new drugs to treat colon cancers with oncogenic KRAS mutations, we examined in this study the efficacy of anti-DLL4 antibodies in KRAS mutant tumors in a panel of early passage colon tumor xenograft models derived from patients. Consistent with clinical findings, mutant KRAS colorectal xenograft tumors were insensitive to the EGFR therapeutic antibody cetuximab, whereas KRAS wild-type tumors responded to cetuximab. In contrast, anti-DLL4 was efficacious against both wild-type and mutant KRAS colon tumors as a single agent and in combination with irinotecan. Further analysis of mutant KRAS tumors indicated that the anti-DLL4/irinotecan combination produced a significant decrease in colon cancer stem cell frequency while promoting apoptosis in tumor cells. Our findings provide a rationale for targeting DLL4-Notch signaling for improved treatment of CRC patients with activating KRAS mutations. PMID:21193546
Fischer, Marcus; Yen, Wan-Ching; Kapoun, Ann M; Wang, Min; O'Young, Gilbert; Lewicki, John; Gurney, Austin; Hoey, Timothy
Predicting mechanism of biphasic growth factor action on tumor growth using a multi-species model with feedback control
A large number of growth factors and drugs are known to act in a biphasic manner: at lower concentrations they cause increased division of target cells, whereas at higher concentrations the mitogenic effect is inhibited. Often, the molecular details of the mitogenic effect of the growth factor are known, whereas the inhibitory effect is not. Hepatoctyte Growth Factor, HGF, has recently been recognized as a strong mitogen that is present in the microenvironment of solid tumors. Recent evidence suggests that HGF acts in a biphasic manner on tumor growth. We build a multi-species model of HGF action on tumor cells using different hypotheses for high dose-HGF activation of a growth inhibitor and show that the shape of the dose-response curve is directly related to the mechanism of inhibitor activation. We thus hypothesize that the shape of a dose-response curve is informative of the molecular action of the growth factor on the growth inhibitor.
Konstorum, Anna; Sprowl, Stephanie A.; Waterman, Marian L.; Lander, Arthur D.; Lowengrub, John S.
Effects of the Tyrosine Kinase Inhibitor Imatinib on Neuroendocrine Tumor Cell Growth
Aim: We investigated the effects of the tyrosine kinase inhibitor imatinib (Gleevec�) on neuroendocrine tumor cells. Methods: Neuroendocrine tumor cells were incubated without and with imatinib. The effects on growth were examined by methylthiazoletetrazolium (MTT) assay. The c-Kit expression in human endocrine tumor tissue and cell lines was determined by immunohistochemistry and Western blot analysis, respectively. Cytotoxicity assay was performed
Brigitte Lankat-Buttgereit; Dieter H�rsch; Peter Barth; Rudolf Arnold; Silke Bl�cker; R�diger G�ke
Impact of Stroma on the Growth, Microcirculation, and Metabolism of Experimental Prostate Tumors
Abstract In prostate cancers (PCa), the formation of malignant stroma may substantially influence tumor phenotype and aggressiveness. Thus, the impact of the orthotopic and subcutaneous implantations of hormone-sensitive (H), hormone-insensitive (HI), and anaplastic (AT1) Dunning PCa in rats on growth, microcirculation, and metabolism was investigated. For this purpose, dynamic contrast-enhanced magnetic resonance imaging and 1H magnetic resonance spectroscopy ([1H]MRS) were applied in combination with histology. Consistent observations revealed that orthotopic H tumors grew significantly slower compared to subcutaneous ones, whereas the growth of HI and AT1 tumors was comparable at both locations. Histologic analysis indicated that glandular differentiation and a close interaction of tumor cells and smooth muscle cells (SMC) were associated with slow tumor growth. Furthermore, there was a significantly lower SMC density in subcutaneous H tumors than in orthotopic H tumors. Perfusion was observed to be significantly lower in orthotopic H tumors than in subcutaneous H tumors. Regional blood volume and permeability-surface area product showed no significant differences between tumor models and their implantation sites. Differences in growth between subcutaneous and orthotopic H tumors can be attributed to tumor-stroma interaction and perfusion. Here, SMC, may stabilize glandular structures and contribute to the maintenance of differentiated phenotype.
Zechmann, Christian M; Woenne, Eva C; Brix, Gunnar; Radzwill, Nicole; Ilg, Martin; Bachert, Peter; Peschke, Peter; Kirsch, Stefan; Kauczor, Hans-Ulrich; Delorme, Stefan; Semmler, Wolfhard; Kiessling, Fabian
Vascular endothelial growth inhibitor (VEGI; TNFSF15) inhibits bone marrow-derived endothelial progenitor cell incorporation into Lewis lung carcinoma tumors
Bone marrow (BM)-derived endothelial progenitor cells (EPC) have a critical role in tumor neovascularization. Vascular endothelial growth inhibitor (VEGI) is a member of the TNF superfamily (TNFSF15). We have shown that recombinant VEGI suppresses tumor angiogenesis by specifically eliminating proliferating endothelial cells (EC). We report here that treatment of tumor bearing mice with recombinant VEGI leads to a significantly decreased population of BM-derived EPC in the tumors. We transplanted whole bone marrow from green fluorescent protein (GFP) transgenic mice into C57BL/6 recipient mice, which were then inoculated with Lewis lung carcinoma (LLC) cells. Intraperitoneal injection of recombinant VEGI led to significant inhibition of tumor growth and decrease of vasculature density compared to vehicle-treated mice. Tumor implantation yielded a decrease of BM-derived EPC in the peripheral blood, while VEGI-treatment resulted in an initial delay of such decrease. Analysis of the whole bone marrow showed a decrease of Lin?-c-Kit+-Sca-1+ hematopoietic stem cell (HSC) population in tumor bearing mice; however, VEGI-treatment caused a significant increase of this cell population. In addition, the number of BM-derived EPC in VEGI-treated tumors was notably less than that in the vehicle-treated group, and most of the apoptotic cells in the VEGI-treated tumors were of bone marrow origin. These findings indicate that VEGI inhibits BM-derived EPC mobilization and prevents their incorporation into LLC tumors by inducing apoptosis specifically of BM-derived cells, resulting in the inhibition of EPC-supported tumor vasculogenesis and tumor growth.
Liang, Paulina H.; Tian, Fang; Lu, Yi; Duan, Biyan; Stolz, Donna B.
The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics
Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo. These findings link, for the first time, the HMGB1�RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression.
Kang, R; Tang, D; Schapiro, NE; Loux, T; Livesey, KM; Billiar, TR; Wang, H; Van Houten, B; Lotze, MT; Zeh, HJ
The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics.
Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo. These findings link, for the first time, the HMGB1-RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression. PMID:23318458
Kang, R; Tang, D; Schapiro, N E; Loux, T; Livesey, K M; Billiar, T R; Wang, H; Van Houten, B; Lotze, M T; Zeh, H J
Evaluating the role of substance P in the growth of brain tumors.
Recent research has investigated the expression and secretion of neuropeptides by tumors, and the potential of these peptides to facilitate tumor growth and spread. In particular, substance P (SP) and its receptor NK1 have been implicated in tumor cell growth and evasion of apoptosis, although few studies have examined this relationship in vivo. The present study used both in vitro and in vivo models to characterize the role of SP in tumor pathogenesis. Immunohistochemical assessment of human primary and secondary brain tumor tissue demonstrated a marked increase in SP and its NK1 receptor in all tumor types investigated. Of the metastatic tumors, melanoma demonstrated particularly elevated SP and NK1 receptor staining. Subsequently, A-375 human melanoma cell line was examined in vitro and found to express both SP and the NK1 receptor. Treatment with the NK1 receptor antagonist Emend IV resulted in decreased cell viability and an increase in cell death in this cell line in vitro. An animal model of brain tumors using the same cell line was employed to assess the effect of Emend IV on tumor growth in vivo. Administration of Emend IV was found to decrease tumor volume and decrease cellular proliferation indicating that SP may play a role in tumor pathogenesis within the brain. We conclude that SP may provide a novel therapeutic target in the treatment of certain types of brain tumors, with further research required to determine whether the role of SP in cancer is tumor-type dependent. PMID:24374326
Harford-Wright, E; Lewis, K M; Vink, R; Ghabriel, M N
Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis.
Prostaglandins derived from the cyclooxygenase (COX) pathway and epoxyeicosatrienoic acids (EETs) from the cytochrome P450/soluble epoxide hydrolase (sEH) pathway are important eicosanoids that regulate angiogenesis and tumorigenesis. COX-2 inhibitors, which block the formation of prostaglandins, suppress tumor growth, whereas sEH inhibitors, which increase endogenous EETs, stimulate primary tumor growth and metastasis. However, the functional interactions of these two pathways in cancer are unknown. Using pharmacological inhibitors as probes, we show here that dual inhibition of COX-2 and sEH synergistically inhibits primary tumor growth and metastasis by suppressing tumor angiogenesis. COX-2/sEH dual pharmacological inhibitors also potently suppress primary tumor growth and metastasis by inhibiting tumor angiogenesis via selective inhibition of endothelial cell proliferation. These results demonstrate a critical interaction of these two lipid metabolism pathways on tumorigenesis and suggest dual inhibition of COX-2 and sEH as a potential therapeutic strategy for cancer therapy. PMID:25024195
Zhang, Guodong; Panigrahy, Dipak; Hwang, Sung Hee; Yang, Jun; Mahakian, Lisa M; Wettersten, Hiromi I; Liu, Jun-Yan; Wang, Yanru; Ingham, Elizabeth S; Tam, Sarah; Kieran, Mark W; Weiss, Robert H; Ferrara, Katherine W; Hammock, Bruce D
M-HIFU Inhibits Tumor Growth, Suppresses STAT3 Activity and Enhances Tumor Specific Immunity in a Transplant Tumor Model of Prostate Cancer
Objective In this study, we explored the use of mechanical high intensity focused ultrasound (M-HIFU) as a neo-adjuvant therapy prior to surgical resection of the primary tumor. We also investigated the role of signal transducer and activator of transcription 3 (STAT3) in M-HIFU elicited anti-tumor immune response using a transplant tumor model of prostate cancer. Methods RM-9, a mouse prostate cancer cell line with constitutively activated STAT3, was inoculated subcutaneously in C57BL/6J mice. The tumor-bearing mice (with a maximum tumor diameter of 5?6 mm) were treated by M-HIFU or sham exposure two days before surgical resection of the primary tumor. Following recovery, if no tumor recurrence was observed in 30 days, tumor rechallenge was performed. The growth of the rechallenged tumor, survival rate and anti-tumor immune response of the animal were evaluated. Results No tumor recurrence and distant metastasis were observed in both treatment groups employing M-HIFU + surgery and surgery alone. However, compared to surgery alone, M-HIFU combined with surgery were found to significantly inhibit the growth of rechallenged tumors, down-regulate intra-tumoral STAT3 activities, increase cytotoxic T cells in spleens and tumor draining lymph nodes (TDLNs), and improve the host survival. Furthermore, M-HIFU combined with surgery was found to significantly decrease the level of immunosuppression with concomitantly increased number and activities of dendritic cells, compared to surgery alone. Conclusion Our results demonstrate that M-HIFU can inhibit STAT3 activities, and when combined synergistically with surgery, may provide a novel and promising strategy for the treatment of prostate cancers.
Huang, Xiaoyi; Yuan, Fang; Liang, Meihua; Lo, Hui-Wen; Shinohara, Mari L.; Robertson, Cary; Zhong, Pei
Tumor STAT1 Transcription Factor Activity Enhances Breast Tumor Growth and Immune Suppression Mediated by Myeloid-derived Suppressor Cells*
Previous studies had implicated the IFN-? transcription factor signal transducer and activator of transcription 1 (STAT1) as a tumor suppressor. However, accumulating evidence has correlated increased STAT1 activation with increased tumor progression in multiple types of cancer, including breast cancer. Indeed, we present evidence that tumor up-regulation of STAT1 activity in human and mouse mammary tumors correlates with increasing disease progression to invasive carcinoma. A microarray analysis comparing low aggressive TM40D and highly aggressive TM40D-MB mouse mammary carcinoma cells revealed significantly higher STAT1 activity in the TM40D-MB cells. Ectopic overexpression of constitutively active STAT1 in TM40D cells promoted mobilization of myeloid-derived suppressor cells (MDSCs) and inhibition of antitumor T cells, resulting in aggressive tumor growth in tumor-transplanted, immunocompetent mice. Conversely, gene knockdown of STAT1 in the metastatic TM40D-MB cells reversed these events and attenuated tumor progression. Importantly, we demonstrate that in human breast cancer, the presence of tumor STAT1 activity and tumor-recruited CD33+ myeloid cells correlates with increasing disease progression from ductal carcinoma in situ to invasive carcinoma. We conclude that STAT1 activity in breast cancer cells is responsible for shaping an immunosuppressive tumor microenvironment, and inhibiting STAT1 activity is a promising immune therapeutic approach.
Hix, Laura M.; Karavitis, John; Khan, Mohammad W.; Shi, Yihui H.; Khazaie, Khashayarsha; Zhang, Ming
A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability
Vascular endothelial growth factor (VEGF) induces both angiogenesis and an increase in vascular permeability, 2 processes that are considered to be important for both tumor growth and the delivery of drugs to the site of tumors. This study demonstrates that transmembrane expression of tumor necrosis factor (tmTNF) is up-regulated in the endothelium of a murine methylcholan- threne (meth A)-induced sarcoma
Matthias Clauss; Cord Sunderkotter; Baldur Sveinbjornsson; Stefan Hippenstiel; Antje Willuweit; Michael Marino; Elvira Haas; Rolf Seljelid; Peter Scheurich; Norbert Suttorp; Matthias Grell; Werner Risau
Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors: II. The role of dysregulated growth factor signaling.
Patients with neurofibromatosis type 1 (NF1), one of the most common genetic disease affecting the nervous system, develop multiple neurofibromas that can transform into aggressive sarcomas known as malignant peripheral nerve sheath tumors (MPNSTs). Studies of human tumors and newly developed transgenic mouse models indicate that Schwann cells are the primary neoplastic cell type in neurofibromas and MPNSTs and that development of these peripheral nerve sheath tumors involves mutations of multiple tumor suppressor genes. However, it is widely held that tumor suppressor mutations alone are not sufficient to induce peripheral nerve sheath tumor formation and that dysregulated growth factor signaling cooperates with these mutations to promote neurofibroma and MPNST tumorigenesis. In Part I of this review, we discussed findings demonstrating that a loss of NF1 tumor suppressor gene function in neoplastic Schwann cells is a key early step in neurofibroma formation and that progression from neurofibroma to MPNST is associated with abnormalities of additional tumor suppressor genes, including p53, INK4A, andp27(kip1). In Part II of this review, we consider evidence that dysregulated signaling by specific growth factors and growth factor receptors promotes the proliferation, migration, and survival of neoplastic Schwann cells in neurofibromas and MPNSTs. PMID:15715079
Carroll, Steven L; Stonecypher, Mark S
Low red/far-red ratios delay spike and stem growth in wheat
The responses to low red light/far-red light (R/FR) ratios simulating dense stands were evaluated in wheat (Triticum aestivum L) cultivars released at different times in the 20th century and consequently resulting from an increasingly prolonged breeding and selection history. While tillering responses to the R/FR ratio were unaffected by the cultivars, low R/FR ratios reduced grain yield per plant (primarily grain number and secondarily grain weight per plant) particularly in modern cultivars. Low R/FR ratios delayed spike growth and development, reduced the expression of spike marker genes, accelerated the development of florets already initiated, and reduced the number of fertile florets at anthesis. It is noteworthy that low R/FR ratios did not promote stem or leaf sheath growth and therefore the observed reduction of yield cannot be accounted for as a consequence of divergence of resources towards increased plant stature. It is proposed that the regulation of yield components by the R/FR ratio could help plants to adjust to the limited availability of resources under crop conditions.
Ugarte, Cristina Cecilia; Trupkin, Santiago Ariel; Ghiglione, Hernan; Slafer, Gustavo; Casal, Jorge Jose
Plasmin-driven fibrinolysis facilitates skin tumor growth in a gender-dependent manner.
Rearrangement of the skin during wound healing depends on plasmin and plasminogen, which serve to degrade fibrin depositions in the provisional matrix and thereby facilitate keratinocyte migration. In the current study, we investigated whether plasmin and plasminogen likewise played a role during the development of skin cancer. To test this, we set up a chemically induced skin tumor model in a cohort of mice and found that skin tumor growth in Plg(-/-) male mice was reduced by 52% compared with wild-type controls. Histological analyses suggested that the growth-restricting effect of plasminogen deficiency was due to thrombosis and lost patency of the tumor vasculature, resulting in tumor necrosis. The connection between plasmin-dependent fibrinolysis, vascular patency, and tumor growth was further substantiated as the effect of plasminogen deficiency on tumor growth could be reverted by superimposing heterozygous fibrinogen deficiency on Plg(-/-) mice. Tumors derived from these Fib(-/+);Plg(-/-) mice displayed a significantly decreased level of tumor thrombosis compared with Plg(-/-) mice. In summary, these data indicate that plasmin-driven fibrinolysis facilitates tumor growth by maintaining patency of the tumor vasculature. PMID:22815383
Hald, Andreas; Eickhardt, Hanne; Maerkedahl, Rasmus Baadsgaard; Feldborg, Christina Winther; Egerod, Kristoffer Lihme; Engelholm, Lars Henning; Laerum, Ole Didrik; Lund, Leif R�ge; R�n�, Birgitte
In vivo delivery of siRNA targeting vasohibin-2 decreases tumor angiogenesis and suppresses tumor growth in ovarian cancer.
Vasohibin-2 (VASH2) is a homolog of vasohibin-1 and exhibits pro-angiogenic activity. We recently reported that VASH2 is expressed in certain ovarian cancers and promotes tumor growth through angiogenesis. To further demonstrate the effectiveness of molecular targeting of VASH2 for anticancer treatment, we applied in vivo delivery of siRNA targeting VASH2 (siVASH2) using atelocollagen to a xenograft model of ovarian cancer. We inoculated mice s.c. with DISS and SKOV-3, two representative human ovarian serous adenocarcinoma cell lines. When tumors were measurable, we initiated treatment with control or siVASH2 mixed with atelocollagen, which enveloped the whole tumor. Treatment with siVASH2 significantly inhibited s.c. tumor growth by abrogating tumor angiogenesis. We confirmed that expression of VASH2 mRNA in the tumor was downregulated by siVASH2 treatment. In addition, the siVASH2-treated tumor contained more blood vessels covered with pericytes, indicating that knockdown of VASH2 contributes to the normalization of tumor blood vessels. Based on these results, VASH2 may be a promising molecular target for ovarian cancer treatment. PMID:24118388
Koyanagi, Takahiro; Suzuki, Yasuhiro; Saga, Yasushi; Machida, Shizuo; Takei, Yuji; Fujiwara, Hiroyuki; Suzuki, Mitsuaki; Sato, Yasufumi
Ohio State study shows how normal cells can fuel tumor growth:
A new study published in the journal Nature Cell Biology has discovered how normal cells in mouse tumors can fuel tumor growth. Led by researchers at the Ohio State University Comprehensive Cancer Center�Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, the study examines what happens when normal cells called fibroblasts in mouse mammary tumors lose an important tumor-suppressor gene called Pten.
Stochastic resonance induced by L�vy noise in a tumor growth model with periodic treatment
NASA Astrophysics Data System (ADS)
In this paper, the stochastic resonance phenomenon in a tumor growth model under subthreshold periodic therapy and L�vy noise excitation is investigated. The possible reoccurrence of tumor due to stochastic resonance is discussed. The signal-to-noise ratio (SNR) is calculated numerically to measure the stochastic resonance. It is found that smaller stability index is better for avoiding tumor reappearance. Besides, the effect of the skewness parameter on the tumor regrowth is related to the stability index. Furthermore, increasing the intensity of periodic treatment does not always facilitate tumor therapy. These results are beneficial to the optimization of periodic tumor therapy.
Xu, Wei; Hao, Mengli; Gu, Xudong; Yang, Guidong
Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma.
Osteosarcoma (OS) is the most common primary malignancy of bone. There is a critical need to identify the events that lead to the poorly understood mechanism of OS development and metastasis. The goal of this investigation is to identify and characterize a novel marker of OS progression. We have established and characterized a highly metastatic OS subline that is derived from the less metastatic human MG63 line through serial passages in nude mice via intratibial injections. Microarray analysis of the parental MG63, the highly metastatic MG63.2 subline, as well as the corresponding primary tumors and pulmonary metastases revealed insulin-like growth factor binding protein 5 (IGFBP5) to be one of the significantly downregulated genes in the metastatic subline. Confirmatory quantitative RT-PCR on 20 genes of interest demonstrated IGFBP5 to be the most differentially expressed and was therefore chosen to be one of the genes for further investigation. Adenoviral mediated overexpression and knockdown of IGFBP5 in the MG63 and MG63.2 cell lines, as well as other OS lines (143B and MNNG/HOS) that are independent of our MG63 lines, were employed to examine the role of IGFBP5. We found that overexpression of IGFBP5 inhibited in vitro cell proliferation, migration and invasion of OS cells. Additionally, IGFBP5 overexpression promoted apoptosis and cell cycle arrest in the G1 phase. In an orthotopic xenograft animal model, overexpression of IGFBP5 inhibited OS tumor growth and pulmonary metastases. Conversely, siRNA-mediated knockdown of IGFBP5 promoted OS tumor growth and pulmonary metastases in vivo. Immunohistochemical staining of patient-matched primary and metastatic OS samples demonstrated decreased IGFBP5 expression in the metastases. These results suggest 1) a role for IGFBP5 as a novel marker that has an important role in the pathogenesis of OS, and 2) that the loss of IGFBP5 function may contribute to more metastatic phenotypes in OS. PMID:21460855
Su, Y; Wagner, E R; Luo, Q; Huang, J; Chen, L; He, B-C; Zuo, G-W; Shi, Q; Zhang, B-Q; Zhu, G; Bi, Y; Luo, J; Luo, X; Kim, S H; Shen, J; Rastegar, F; Huang, E; Gao, Y; Gao, J-L; Yang, K; Wietholt, C; Li, M; Qin, J; Haydon, R C; He, T-C; Luu, H H
Hyperbolastic modeling of tumor growth with a combined treatment of iodoacetate and dimethylsulphoxide
Background An understanding of growth dynamics of tumors is important in understanding progression of cancer and designing appropriate treatment strategies. We perform a comparative study of the hyperbolastic growth models with the Weibull and Gompertz models, which are prevalently used in the field of tumor growth. Methods The hyperbolastic growth models H1, H2, and H3 are applied to growth of solid Ehrlich carcinoma under several different treatments. These are compared with results from Gompertz and Weibull models for the combined treatment. Results The growth dynamics of the solid Ehrlich carcinoma with the combined treatment are studied using models H1, H2, and H3, and the models are highly accurate in representing the growth. The growth dynamics are also compared with the untreated tumor, the tumor treated with only iodoacetate, and the tumor treated with only dimethylsulfoxide, and the combined treatment. Conclusions The hyperbolastic models prove to be effective in representing and analyzing the growth dynamics of the solid Ehrlich carcinoma. These models are more precise than Gompertz and Weibull and show less error for this data set. The precision of H3 allows for its use in a comparative analysis of tumor growth rates between the various treatments.
Inoculated mammary carcinoma-associated fibroblasts: contribution to hormone independent tumor growth
Background Increasing evidence has underscored the role of carcinoma associated fibroblasts (CAF) in tumor growth. However, there are controversial data regarding the persistence of inoculated CAF within the tumors. We have developed a model in which murine metastatic ductal mammary carcinomas expressing estrogen and progesterone receptors transit through different stages of hormone dependency. Hormone dependent (HD) tumors grow only in the presence of progestins, whereas hormone independent (HI) variants grow without hormone supply. We demonstrated previously that CAF from HI tumors (CAF-HI) express high levels of FGF-2 and that FGF-2 induced HD tumor growth in vivo. Our main goal was to investigate whether inoculated CAF-HI combined with purified epithelial (EPI) HD cells can induce HD tumor growth. Methods Purified EPI cells of HD and HI tumors were inoculated alone, or together with CAF-HI, into female BALB/c mice and tumor growth was evaluated. In another set of experiments, purified EPI-HI alone or combined with CAF-HI or CAF-HI-GFP were inoculated into BALB/c or BALB/c-GFP mice. We assessed whether inoculated CAF-HI persisted within the tumors by analyzing inoculated or host CAF in frozen sections of tumors growing in BALB/c or BALB/c-GFP mice. The same model was used to evaluate early stages of tumor development and animals were euthanized at 2, 7, 12 and 17 days after EPI-HI or EPI-HI+CAF-HI inoculation. In angiogenesis studies, tumor vessels were quantified 5 days after intradermal inoculation. Results We found that admixed CAF-HI failed to induce epithelial HD tumor growth, but instead, enhanced HI tumor growth (p < 0.001). Moreover, inoculated CAF-HI did not persist within the tumors. Immunofluorescence studies showed that inoculated CAF-HI disappeared after 13 days. We studied the mechanisms by which CAF-HI increased HI tumor growth, and found a significant increase in angiogenesis (p < 0.05) in the co-injected mice at early time points. Conclusions Inoculated CAF-HI do not persist within the tumor mass although they play a role during the first stages of tumor formation promoting angiogenesis. This angiogenic environment is unable to replace the hormone requirement of HD tumors that still need the hormone to recruit the stroma from the host.
p62/SQSTM1 synergizes with autophagy for tumor growth in vivo.
Autophagy is crucial for cellular homeostasis and plays important roles in tumorigenesis. FIP200 (FAK family-interacting protein of 200 kDa) is an essential autophagy gene required for autophagy induction, functioning in the ULK1-ATG13-FIP200 complex. Our previous studies showed that conditional knockout of FIP200 significantly suppressed mammary tumorigenesis, which was accompanied by accumulation of p62 in tumor cells. However, it is not clear whether FIP200 is also required for maintaining tumor growth and how the increased p62 level affects the growth in autophagy-deficient FIP200-null tumors in vivo. Here, we describe a new system to delete FIP200 in transformed mouse embryonic fibroblasts as well as mammary tumor cells following their transplantation and show that ablation of FIP200 significantly reduced growth of established tumors in vivo. Using similar strategies, we further showed that either p62 knockdown or p62 deficiency in established FIP200-null tumors dramatically impaired tumor growth. The stimulation of tumor growth by p62 accumulation in FIP200-null tumors is associated with the up-regulated activation of the NF-?B pathway by p62. Last, we showed that overexpression of the autophagy master regulator TFEB(S142A) increased the growth of established tumors, which correlated with the increased autophagy of the tumor cells. Together, our studies demonstrate that p62 and autophagy synergize to promote tumor growth, suggesting that inhibition of both pathways could be more effective than targeting either alone for cancer therapy. PMID:24888590
Wei, Huijun; Wang, Chenran; Croce, Carlo M; Guan, Jun-Lin
IL-17A produced by ?? T cells promotes tumor growth in hepatocellular carcinoma.
Interleukin (IL)-17A is expressed in the tumor microenvironment where it appears to contribute to tumor development, but its precise role in tumor immunity remains controversial. Here, we report mouse genetic evidence that IL-17A is critical for tumor growth. IL-17A-deficient mice exhibited reduced tumor growth, whereas systemic administration of recombinant mouse IL-17A promoted the growth of hepatocellular carcinoma. The tumor-promoting effect of IL-17A was mediated through suppression of antitumor responses, especially CD8(+) T-cell responses. Furthermore, we found that IL-17A was produced mainly by V?4 ?? T cells, insofar as depleting V?4 ?? T cells reduced tumor growth, whereas adoptive transfer of V?4 ?? T cells promoted tumor growth. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2-dependent manner. IL-17A also promoted the suppressive activity of MDSC to reinforce suppression of tumoral immunity. Moreover, we found that MDSC could induce IL-17A-producing ?? T cells via production of IL-1? and IL-23. Conversely, IL-17A could also enhance production of IL-1? and IL-23 in MDSC as a positive feedback. Together, our results revealed a novel mechanism involving cross-talk among ?? T cells, MDSCs, and tumor cells through IL-17A production. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy. PMID:24525743
Ma, Shoubao; Cheng, Qiao; Cai, Yifeng; Gong, Huanle; Wu, Yan; Yu, Xiao; Shi, Liyun; Wu, Depei; Dong, Chen; Liu, Haiyan
Significance of vascular endothelial growth factor/vascular permeability factor for solid tumor growth, and its inhibition by the antibody.
Angiogenesis is essential for successful tumor growth in vivo. There is a hypothesis that tumors secrete a putative tumor angiogenic factor (TAF) to facilitate blood vessel formations. Although several endothelial growth factors have been reported, it remains unclear whether these factors function as TAF in vivo. Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) is a vascular endothelial mitogen that can increase blood vessel permeability. We have established a cell line (HeLa/v5), which secretes VEGF/VPF, by transfection of human VEGF/VPF cDNA. HeLa/v5 showed higher angiogenic activity, taken/planted ratio and tumor growth rate than the control transformant (HeLa/c), when they were implanted to nude mice. Administration of a polyclonal antibody, which neutralizes the mitogenic activity of VEGF/VPF in vitro, to the tumor implanted nude mice suppressed the in vivo growth of HeLa/v5. Furthermore, all 8 tumor cell lines we tested secrete VEGF/VPF into culture media. Our findings indicate that VEGF/VPF is a tumor angiogenic factor. PMID:7688963
Kondo, S; Asano, M; Suzuki, H
The role of recombinant epidermal growth factor and serotonin in the stimulation of tumor growth in a SCCHN xenograft model
One challenge of squamous cell carcinoma of the head and neck (SCCHN) chemotherapy is a small percentage of tumor cells that arrest in the G0 phase of the cell cycle and are thus not affected by chemotherapy. This could be one reason for tumor recurrence at a later date. The recruitment of these G0-arresting cells into the active cell cycle and thus, proliferation, may increase the efficacy of chemotherapeutic agents. The aim of this study was to investigate whether stimulation with recombinant epidermal growth factor (EGF) or serotonin leads to an increased tumor cell proliferation in xenografts. Detroit 562 cells were injected into NMRI-Foxn1nu mice. Treatment was performed with 15 ?g murine or human EGF, or 200 ?g serotonin. The control mice were treated with Lactated Ringer�s solution (5 mice/group). Tumor size was measured on days 4, 8 and 12 after tumor cell injection. The EGF stimulated mice showed a significantly higher tumor growth compared to the serotonin-stimulated mice and the untreated controls. In the present study, we show that it is possible to stimulate tumor cells in xenografts by EGF and thus, enhance cell proliferation, resulting in a higher tumor growth compared to the untreated control group. In our future investigations, we plan to include a higher number of mice, an adjustment of the EGF dosage and cell subanalysis, considering the heterogeneity of SCCHN tumors.
Overexpression of Notch ligand Dll1 in B16 melanoma cells leads to reduced tumor growth due to attenuated vascularization.
Notch signaling plays an important role in vascular development and tumor angiogenesis. It has been shown that disruption of Dll4-triggered Notch signal activation effectively inhibits tumor growth, but this treatment also results in the formation of vascular neoplasms. In this study, we investigate the effects of over-expressing Notch ligand Dll1 in B16 melanoma cells on tumor cell proliferation and tumor growth in vitro and in vivo. Our results showed that over-expression of Dll1 could activate Notch signaling in tumor cells, and promote tumor cell proliferation in vitro. In contrast, growth of Dll1-over-expressing tumors in vivo was reduced, due to abnormal tumor vessel formation. Impaired tumor vasculature enhanced hypoxia and necrosis in tumor tissues, leading to retarded tumor growth. These results suggest that activation of Notch signaling may serve as an anti-angiogenesis strategy in the treatment of malignant tumors. PMID:21752535
Zhang, Jian-Ping; Qin, Hong-Yan; Wang, Li; Liang, Liang; Zhao, Xing-Cheng; Cai, Wei-Xia; Wei, Ya-Ning; Wang, Chun-Mei; Han, Hua
Phenotypic variation in constitutional delay of growth and puberty: relationship to specific leptin and leptin receptor gene polymorphisms
Objectives: Constitutional delay of growth and puberty (CDGP) is a variant of normal pubertal timing and progress, often with dominant inheritance. It is likely that one or more genes will be associated with CDGP. Possible candidates are the leptin (L) and the leptin receptor (LR) genes, as the leptin axis links nutritional status to pubertal development. This study has assessed
Indraneel Banerjee; Julie A Trueman; Catherine M Hall; David A Price; Leena Patel; Andrew J Whatmore; Joel N Hirschhorn; Andrew P Read; Mark R Palmert; Peter E Clayton
Clinically Relevant Doses of Candesartan Inhibit Growth of Prostate Tumor Xenografts In Vivo through Modulation of Tumor Angiogenesis.
Angiotensin II receptor type 1 blockers (ARBs), widely used antihypertensive drugs, have also been investigated for their anticancer effects. The effect of ARBs on prostate cancer in experimental models compared with meta-analysis data from clinical trials is conflicting. Whereas this discrepancy might be due to the use of supratherapeutic doses of ARBs in cellular and animal models as compared with the clinical doses used in human trials, further investigation of the effects of clinical doses of ARBs on prostate cancer in experimental models is warranted. In the current study, we sought to determine the effects of candesartan on prostate cancer cellular function in vitro and tumor growth in vivo, and characterize the underlying mechanisms. Our analysis indicated that clinically relevant doses of candesartan significantly inhibited growth of PC3 cell tumor xenografts in mice. Interestingly, the same concentrations of candesartan actually promoted prostate cancer cellular function in vitro, through a modest but significant inhibition in apoptosis. Inhibition of tumor growth by candesartan was associated with a decrease in vascular endothelial growth factor (VEGF) expression in tumors and inhibition of tumor angiogenesis, but normalization of tumor vasculature. Although candesartan did not impair PC3 cell viability, it inhibited endothelial-barrier disruption by tumor-derived factors. Furthermore, candesartan significantly inhibited expression of VEGF in PC3 and DU145 cell lines independent of angiotensin II type 2 receptor, but potentially via angiotensin II type 1 receptor inhibition. Our findings clearly demonstrate the therapeutic potential of candesartan for prostate cancer and establish a link between ARBs, VEGF expression, and prostate tumor angiogenesis. PMID:24990940
Alhusban, Ahmed; Al-Azayzih, Ahmad; Goc, Anna; Gao, Fei; Fagan, Susan C; Somanath, Payaningal R
Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma.
Preclinical studies have suggested that sunitinib accelerates metastases in animals, ascribing this to inhibition of the vascular endothelial growth factor receptor or the tumor's adaptation. To address whether sunitinib accelerates tumors in humans, we analyzed data from the pivotal randomized phase III trial comparing sunitinib and interferon alfa in patients with metastatic renal cell carcinoma. The evidence clearly shows that sunitinib was not harmful, did not accelerate tumor growth, and did not shorten survival. Specifically, neither longer sunitinib treatment nor a greater effect of sunitinib on tumors reduced survival. Sunitinib did reduce the tumor's growth rate while administered, thereby improving survival, without appearing to alter tumor biology after discontinuation. Concerns arising from animal models do not apply to patients receiving sunitinib and likely will not apply to similar agents. PMID:23395639
Blagoev, Krastan B; Wilkerson, Julia; Stein, Wilfred D; Motzer, Robert J; Bates, Susan E; Fojo, A Tito
Block of purinergic P2X7R inhibits tumor growth in a C6 glioma brain tumor animal model.
We examined the expression and pharmacological modulation of the purinergic receptor P2X7R in a C6 glioma model. Intrastriatal injection of C6 cells induced a time-dependent growth of tumor; at 2 weeks postinjection immunohistochemical analysis demonstrated higher levels of P2X7R in glioma-injected versus control vehicle-injected brains. P2X7R immunoreactivity colocalized with tumor cells and microglia, but not endogenous astrocytes. Intravenous administration of the P2X7R antagonist brilliant blue G (BBG) inhibited tumor growth in a spatially dependent manner from the C6 injection site. Treatment with BBG reduced tumor volume by 52% versus that in controls. Double immunostaining indicated that BBG treatment did not alter microgliosis, astrogliosis, or vasculature vessels in C6-injected animals. In vitro, BBG reduced the expression of P2X7R and glioma chemotaxis induced by the P2X7R ligand, 2',3'-O-(4-benzoyl-benzoyl)adenosine triphosphate (BzATP). Immunohistochemical staining of human glioblastoma tissue samples demonstrated greater expression of P2X7R compared to control nontumor samples. These results suggest that the efficacy of BBG in inhibiting tumor growth is primarily mediated by direct actions of the compound on P2X7R in glioma cells and that pharmacological inhibition of this purinergic receptor might serve as a strategy to slow the progression of brain tumors. PMID:21157381
Ryu, Jae K; Jantaratnotai, Nattinee; Serrano-Perez, Maria C; McGeer, Patrick L; McLarnon, James G
Antiangiogenic Therapy Using Sunitinib Combined with Rapamycin Retards Tumor Growth But Promotes Metastasis1
BACKGROUND: This study investigated the synergistic effect of sunitinib and rapamycin on tumor growth and metastasis in murine breast cancer model. METHODS: The synergistic antitumor effect of sunitinib and rapamycin on tumor growth and metastasis was investigated. Myeloid-derived suppressor cells (MDSCs) in spleens and lungs were assessed. Tumor hypoxia, vessel density and micrometastasis were evaluated. Versican, indoleamine 2,3-dioxygenase (IDO), arginase 1, interleukin-6 (IL-6), IL-10, and transforming growth factor ? (TGF-?) in the lungs and tumors were examined. IL-6 and TGF-? in the blood were evaluated. RESULTS: Synergism between sunitinib and rapamycin on tumor growth was observed. Sunitinib plus rapamycin reduced splenomegaly, MDSCs in spleens and lungs, and microvessel density in tumor microenvironment, while exacerbated hypoxia and promoted cancer lung metastasis. Sunitinib plus rapamycin markedly induced versican, IDO, arginase 1, IL-6, and TGF-? expression in the lungs, whereas it reduced IDO and IL-10 expression in the primary tumor tissues. IL-6 levels in the circulation were increased after rapamycin and combination therapies. CONCLUSIONS: The combination of sunitinib plus rapamycin reduced the tumor growth but promoted tumor metastasis. This study warrants that further mTOR inhibition treatment should be closely watched in clinical setting, especially combined with antiangiogenic therapy.
Yin, Tao; He, Sisi; Ye, Tinghong; Shen, Guobo; Wan, Yang; Wang, Yongsheng
Trichinella spiralis infection reduces tumor growth and metastasis of B16-F10 melanoma cells.
Recently, attempts have been made to use parasites as novel candidates for live vaccine vectors against solid tumors. In this study, we examined the effects of Trichinella spiralis (T. spiralis) infection on solid tumor growth and metastasis. After oral infection with T. spiralis larvae, B16-F10 cells were injected subcutaneously and intravenously into C57BL/6 mice to evaluate tumor growth and metastatic potential, respectively. Tumor growth and lung metastases in T. spiralis infected mice were significantly reduced compared with control mice. To elucidate the mechanism of tumor reduction by parasitic infection, we conducted cytokine arrays using mouse serum. CXCL9 and CXCL10 were increased in the infection group and decreased in the infection-tumor group. However, the expression level was not changed in the infection-metastasis group compared to the infection or control-metastasis groups. Although SDF-1 and IL-4 were increased in the infection group, there was no significant change in expression in the infection-tumor group or the infection-metastasis group. Additionally, IL-4 and KC were increased in the infection-tumor group compared to the control-tumor group, but there was no difference in expression between the control-metastasis group and the infection-metastasis group. CXCL13 was significantly increased in the infection-metastasis group only. These results suggest that T. spiralis infection reduced tumor growth and metastasis through a complex transition in cytokine regulation profiles including CXCL9, CXCL10, and CXCL13. PMID:23499484
Kang, Yun-Jeong; Jo, Jin-Ok; Cho, Min-Kyoung; Yu, Hak-Sun; Leem, Sun-Hee; Song, Kyoung Seob; Ock, Mee Sun; Cha, Hee-Jae
Reduced tumor growth after low-dose irradiation or immunization against blastic suppressor T cells.
Suppressor T cells have been shown to be much more radiosensitive than other lympho�d cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and other develop smaller tumors than control mice. These results could be explained by the induction of antiidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T10.
Tilkin, A F; Schaaf-Lafontaine, N; Van Acker, A; Boccadoro, M; Urbain, J
Stromal estrogen receptor-? promotes tumor growth by normalizing an increased angiogenesis.
Estrogens directly promote the growth of breast cancers that express the estrogen receptor ? (ER?). However, the contribution of stromal expression of ER? in the tumor microenvironment to the protumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17?-estradiol (E2) impacts the microenvironment and modulates tumor development of ER?-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density, and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ER?-deficient mice, showing a critical role of host ER?. Notably, E2 did not accelerate tumor growth when ER? was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ER?-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ER?-negative cancer cells through the activation of stromal ER? (extra-hematopoietic Tie-2 positive cells), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumors, thereby preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment. PMID:22523036
P�queux, Christel; Raymond-Letron, Isabelle; Blacher, Silvia; Boudou, Fr�d�ric; Adlanmerini, Marine; Fouque, Marie-Jos�; Rochaix, Philippe; No�l, Agn�s; Foidart, Jean-Michel; Krust, Andr�e; Chambon, Pierre; Brouchet, Laurent; Arnal, Jean-Fran�ois; Lenfant, Fran�oise
Reduced tumor growth after low-dose irradiation or immunization against blastic suppressor T cells
Suppressor T cells have been shown to be much more radiosensitive than other lymphoid cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and others develop smaller tumors than control mice. These results could be explained by the induction of antidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T10.
Tilkin, A.F. (Universite Libre de Bruxelles, Belgium); Schaaf-Lafontaine, N.; Van Acker, A.; Boccadoro, M.; Urbain, J.
Reduced Tumor Growth after Low-Dose Irradiation or Immunization against Blastic Suppressor T Cells
NASA Astrophysics Data System (ADS)
Suppressor T cells have been shown to be much more radiosensitive than other lymphoid cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and others develop smaller tumors than control mice. These results could be explained by the induction of antiidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T10.
Tilkin, A. F.; Schaaf-Lafontaine, N.; van Acker, A.; Boccadoro, M.; Urbain, J.
Adnectin CT-322 inhibits tumor growth and affects microvascular architecture and function in Colo205 tumor xenografts.
Antiangiogenesis has become a promising pillar in modern cancer therapy. This study investigates the antiangiogenic effects of the PEGylated Adnectin�, CT-322, in a murine Colo-205 xenograft tumor model. CT-322 specifically binds to and blocks vascular endothelial growth factor receptor (VEGFR-2). Adnectins are a novel class of targeted biologics engineered from the 10th domain of human fibronectin. CT-322 treated tumors exhibited a significant reduction in tumor growth of 69%, a 2.8 times lower tumor surface area and fewer necrotic areas. Control tumors showed a 2.36-fold higher microvessel density (MVD) and a 2.42 times higher vessel volume in corrosion casts. The vascular architecture in CT-322-treated tumors was characterized by a strong normalization of vasculature. This was quantified in corrosion casts of CT-322 treated tumors in which the intervascular distance (a reciprocal parameter indicative of vessel density) and the distance between two consecutive branchings were assessed, with these distances being 2.21 times and 2.37 times greater than in controls, respectively. Fluorescence molecular tomography (FMT) equally affirmed the inhibitory effects of CT-322 on tumor vasculature as indicated by a 60% reduction of the vascular probe, AngioSense, accumulating in tumor tissue, as a measurement of vascular permeability. Moreover, AngioSense accumulation was reduced as early as 24 h after starting treatment. The sum of these effects on tumor vasculature illustrates the anti-angiogenic mechanism underlying the antitumor activity of CT-322 and provides support for further evaluation of this Adnectin in combinatorial strategies with standard of care therapies. PMID:21109927
Ackermann, Maximilian; Carvajal, Irvith M; Morse, Brent A; Moreta, Miguel; O'Neil, Steven; Kossodo, Sylvie; Peterson, Jeffrey D; Delventhal, Vera; Marsh, H Nicholas; Furfine, Eric S; Konerding, Moritz A
CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice.
CD73 is overexpressed in many types of human and mouse cancers and is implicated in the control of tumor progression. However, the specific contribution from tumor or host CD73 expression to tumor growth remains unknown to date. Here, we show that host CD73 promotes tumor growth in a T cell-dependent manner and that the optimal antitumor effect of CD73 blockade requires inhibiting both tumor and host CD73. Notably, enzymatic activity of CD73 on nonhematopoietic cells limited tumor-infiltrating T cells by controlling antitumor T cell homing to tumors in multiple mouse tumor models. In contrast, CD73 on hematopoietic cells (including CD4?CD25? Tregs) inhibited systemic antitumor T cell expansion and effector functions. Thus, CD73 on hematopoietic and nonhematopoietic cells has distinct adenosinergic effects in regulating systemic and local antitumor T cell responses. Importantly, pharmacological blockade of CD73 using its selective inhibitor or an anti-CD73 mAb inhibited tumor growth and completely restored efficacy of adoptive T cell therapy in mice. These findings suggest that both tumor and host CD73 cooperatively protect tumors from incoming antitumor T cells and show the potential of targeting CD73 as a cancer immunotherapy strategy. PMID:21537079
Wang, Long; Fan, Jie; Thompson, Linda F; Zhang, Yi; Shin, Tahiro; Curiel, Tyler J; Zhang, Bin
Giant cell tumor of the lumbar spine with intraperitoneal growth: case report and review of literature.
Giant cell tumors of the spine are uncommon. Usually they are benign and solitary, but locally very aggressive. Most of them occur at the sacral spine. There are only 26 reported cases in the literature involving this type of tumor in the lumbar spine, in particular exhibiting an intraperitoneal growth. We present the case of a woman with a primary tumor of the lumbar spine (giant cell tumor) with intraperitoneal growth, the outcome as well as a review of the literature. Furthermore, after reviewing all spinal cases in the literature above the sacral spine, we carefully suggest a management algorithm. PMID:23615800
Munoz-Bendix, C; Cornelius, J F; Bostelmann, R; Gierga, K; Steiger, H J
Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling
Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and {beta}-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.
Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie [Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 (United States)] [Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 (United States); Oakley, Gregory G.; Wahl, James K. [Department of Oral Biology, University of Nebraska College of Dentistry, Lincoln, NE 68588 (United States)] [Department of Oral Biology, University of Nebraska College of Dentistry, Lincoln, NE 68588 (United States); Simpson, Melanie A., E-mail: email@example.com [Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 (United States); Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198 (United States)
Control of Tumor Growth in Animals by Infusion of an Angiogenesis Inhibitor
NASA Astrophysics Data System (ADS)
Angiogenesis and tumor growth were inhibited in two different animal models by regional infusion of a partially purified cartilage extract. In rabbits bearing corneal implants of V2 carcinoma and receiving the inhibitor, vascular growth rates were <3% of those in control animals receiving either Ringer's solution or bovine trypsin inhibitor (Trasylol). Subconjunctival B16 melanoma implants in mice receiving the inhibitor weighed <2.5% of implants in mice receiving Ringer's solution, Trasylol, or albumin. Histologic study of major organs and standard blood tests revealed no toxic effects in any of the animals. The inhibitor did not retard the growth of either tumor cell type in tissue culture at concentrations as high as 1 mg/ml. These results suggest that the cartilage factor does not interfere with the growth of the tumor cell population directly but that it prevents tumor growth by inhibiting angiogenesis.
Langer, Robert; Conn, Howard; Vacanti, Joseph; Haudenschild, Christian; Folkman, Judah
Sudden cold temperature delays plant carbon transport and shifts allocation from growth to respiratory demand
NASA Astrophysics Data System (ADS)
Since substrates for respiration are supplied mainly by recent photo-assimilates, there is a strong but time-lagged link between short-term above- and belowground carbon (C) cycling. However, regulation of this coupling by environmental variables is poorly understood. Whereas recent studies focussed on the effect of drought and shading on the link between above- and belowground short-term C cycling, the effect of temperature remains unclear. We used a 13CO2 pulse-chase labelling experiment to investigate the effect of a sudden temperature change from 25 to 10 �C on the short-term coupling between assimilatory C uptake and respiratory loss. The study was done in the laboratory using two-month-old perennial rye-grass plants (Lolium perenne L.). After label application, the ?13C signal of respired shoot and root samples was analysed at regular time intervals using laser spectroscopy. In addition, ?13C was analysed in bulk root and shoot samples. Cold temperature (10 �C) reduced the short-term coupling between shoot and roots by delaying belowground transfer of recent assimilates and its subsequent respiratory use, as indicated by the ?13C signal of root respiration (?13CRR). That is, the time lag from the actual shoot labelling to the first appearance of the label in 13CRR was about 1.5 times longer under cold temperature. Moreover, analysis of bulk shoot and root material revealed that plants at cold temperature invest relatively more carbon into respiration compared to growth or storage. While the whole plant C turnover increased under cold temperature, the turnover time of the labile C pool decreased, probably because less 13C is used for growth and/or storage. That is, (almost) all recent C remained in the labile pool serving respiration under these conditions. Overall, our results highlight the importance of temperature as a driver of C transport and relative C allocation within the plant-soil system.
Barthel, M.; Cieraad, E.; Zakharova, A.; Hunt, J. E.
Senescence Mediates Pituitary Hypoplasia and Restrains Pituitary Tumor Growth
Understanding factors subserving pituitary cell proliferation enables understanding mechanisms underlying uniquely benign pituitary tumors. Pituitary tumor-transforming gene (Pttg) deletion results in pituitary hypoplasia, low pituitary cell proliferation rates, and rescue of pituitary tumor development in Rb+\\/ mice. Pttg\\/ pituitary glands exhibit ARF\\/p53\\/p21-dependent senescence pathway activation evidenced by up-regulated p19, cyclin D1, and Bcl-2 protein levels and p53 stabilization. High pituitary
Vera Chesnokova; Svetlana Zonis; Tami Rubinek; Kalman Kovacs; Kolja Wawrowsky; Shlomo Melmed
Mice Lacking NCF1 Exhibit Reduced Growth of Implanted Melanoma and Carcinoma Tumors
The NADPH oxidase 2 (NOX2) complex is a professional producer of reactive oxygen species (ROS) and is mainly expressed in phagocytes. While the activity of the NOX2 complex is essential for immunity against pathogens and protection against autoimmunity, its role in the development of malignant tumors remains unclear. We compared wild type and Ncf1m1J mutated mice, which lack functional NOX2 complex, in four different tumor models. Ncf1m1J mutated mice developed significantly smaller tumors in two melanoma models in which B16 melanoma cells expressing a hematopoietic growth factor FLT3L or luciferase reporter were used. Ncf1m1J mutated mice developed significantly fewer Lewis Lung Carcinoma (LLC) tumors, but the tumors that did develop, grew at a pace that was similar to the wild type mice. In the spontaneously arising prostate carcinoma model (TRAMP), tumor growth was not affected. The lack of ROS-mediated protection against tumor growth was associated with increased production of immunity-associated cytokines. A significant increase in Th2 associated cytokines was observed in the LLC model. Our present data show that ROS regulate rejection of the antigenic B16-luc and LLC tumors, whereas the data do not support a role for ROS in growth of intrinsically generated tumors.
Kelkka, Tiina; Pizzolla, Angela; Laurila, Juha Petteri; Friman, Tomas; Gustafsson, Renata; Kallberg, Eva; Olsson, Olof; Leanderson, Tomas; Rubin, Kristofer; Salmi, Marko; Jalkanen, Sirpa; Holmdahl, Rikard
Gene Transfer of Thromboxane A2 Synthase and Prostaglandin I2 Synthase Antithetically Altered Tumor Angiogenesis and Tumor Growth1
Cyclooxygenase, involved in tumor growth and angiogenesis, converts arachidonic acid to prostaglandin (PG)H2, which is immediately con- verted to bioactive prostanoids including PGE2, PGD2, thromboxane (TX)A2 and PGI2. To test the hypothesis that changes in the prostanoid profile alter cancer growth, we transduced the retroviral vectors carrying TXA2 synthase cDNA or PGI2 synthase cDNA to colon-26 adenocarci- noma cells and
Prasenohadi Pradono; Ryushi Tazawa; Makoto Maemondo; Masashi Tanaka; Kazuhiro Usui; Yasuo Saijo; Koichi Hagiwara; Toshihiro Nukiwa
The Effect of Electroacupuncture on Osteosarcoma Tumor Growth and Metastasis: Analysis of Different Treatment Regimens
Osteosarcoma is the most common malignant bone tumor found in children and adolescents and is associated with many complications including cancer pain and metastasis. While cancer patients often seek complementary and alternative medicine (CAM) approaches to treat cancer pain and fatigue or the side effects of chemotherapy and treatment, there is little known about the effect of acupuncture treatment on tumor growth and metastasis. Here we evaluate the effects of six different electroacupuncture (EA) regimens on osteosarcoma tumor growth and metastasis in both male and female mice. The most significant positive effects were observed when EA was applied to the ST-36 acupoint twice weekly (EA-2X/3) beginning at postimplantation day 3 (PID 3). Twice weekly treatment produced robust reductions in tumor growth. Conversely, when EA was applied twice weekly (EA-2X/7), starting at PID 7, there was a significant increase in tumor growth. We further demonstrate that EA-2X/3 treatment elicits significant reductions in tumor lymphatics, vasculature, and innervation. Lastly, EA-2X/3 treatment produced a marked reduction in pulmonary metastasis, thus providing evidence for EA's potential antimetastatic capabilities. Collectively, EA-2X/3 treatment was found to reduce both bone tumor growth and lung metastasis, which may be mediated in part through reductions in tumor-associated vasculature, lymphatics, and innervation.
Smeester, Branden A.; O'Brien, Elaine E.; Ericson, Marna E.; Triemstra, Jennifer L.; Beitz, Alvin J.
Regulation of Tumor Growth and Metastasis: The Role of Tumor Microenvironment
The presence of abnormal cells with malignant potential or neoplastic characteristics is a relatively common phenomenon. The interaction of these abnormal cells with their microenvironment is essential for tumor development, protection from the body�s immune or defence mechanisms, later progression and the development of life-threatening or metastatic disease. The tumor microenvironment is a collective term that includes the tumor�s surrounding and supportive stroma, the different effectors of the immune system, blood platelets, hormones and other humoral factors. A better understanding of the interplay between the tumor cells and its microenvironment can provide efficient tools for cancer management, as well as better prevention, screening and risk assessment protocols.
Goubran, Hadi A; Kotb, Rami R; Stakiw, Julie; Emara, Mohamed E; Burnouf, Thierry
Therapeutic effects of intrabone and systemic mesenchymal stem cell cytotherapy on myeloma bone disease and tumor growth.
The cytotherapeutic potential of mesenchymal stem cells (MSCs) has been evaluated in various disorders including those involving inflammation, autoimmunity, bone regeneration, and cancer. Multiple myeloma (MM) is a systemic malignancy associated with induction of osteolytic lesions that often are not repaired even after prolonged remission. The aims of this study were to evaluate the effects of intrabone and systemic injections of MSCs on MM bone disease, tumor growth, and tumor regrowth in the severe combined immunodeficiency (SCID)-rab model and to shed light on the exact localization of systemically injected MSCs. Intrabone injection of MSCs, but not hematopoietic stem cells, into myelomatous bones prevented MM-induced bone disease, promoted bone formation, and inhibited MM growth. After remission was induced with melphalan treatment, intrabone-injected MSCs promoted bone formation and delayed myeloma cell regrowth in bone. Most intrabone or systemically injected MSCs were undetected 2 to 4 weeks after injection. The bone-building effects of MSCs were mediated through activation of endogenous osteoblasts and suppression of osteoclast activity. Although a single intravenous injection of MSCs had no effect on MM, sequential weekly intravenous injections of MSCs prevented MM-induced bone disease but had no effect on tumor burden. MSCs expressed high levels of anti-inflammatory (eg, HMOX1) and bone-remodeling (eg, Decorin, CYR61) mediators. In vitro, MSCs promoted osteoblast maturation and suppressed osteoclast formation, and these effects were partially prevented by blocking decorin. A subset of intravenously or intracardially injected MSCs trafficked to myelomatous bone in SCID-rab mice. Although the majority of intravenously injected MSCs were trapped in lungs, intracardially injected MSCs were mainly localized in draining mesenteric lymph nodes. This study shows that exogenous MSCs act as bystander cells to inhibit MM-induced bone disease and tumor growth and that systemically injected MSCs are attracted to bone by myeloma cells or conditions induced by MM and inhibit bone disease. PMID:22460389
Li, Xin; Ling, Wen; Khan, Sharmin; Yaccoby, Shmuel
Pharmacological Inhibition of Microsomal Prostaglandin E Synthase-1 Suppresses Epidermal Growth Factor Receptor-Mediated Tumor Growth and Angiogenesis
Background Blockade of Prostaglandin (PG) E2 production via deletion of microsomal Prostaglandin E synthase-1 (mPGES-1) gene reduces tumor cell proliferation in vitro and in vivo on xenograft tumors. So far the therapeutic potential of the pharmacological inhibition of mPGES-1 has not been elucidated. PGE2 promotes epithelial tumor progression via multiple signaling pathways including the epidermal growth factor receptor (EGFR) signaling pathway. Methodology/Principal Findings Here we evaluated the antitumor activity of AF3485, a compound of a novel family of human mPGES-1 inhibitors, in vitro and in vivo, in mice bearing human A431 xenografts overexpressing EGFR. Treatment of the human cell line A431 with interleukin-1beta (IL-1?) increased mPGES-1 expression, PGE2 production and induced EGFR phosphorylation, and vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expression. AF3485 reduced PGE2 production, both in quiescent and in cells stimulated by IL-1?. AF3485 abolished IL-1?-induced activation of the EGFR, decreasing VEGF and FGF-2 expression, and tumor-mediated endothelial tube formation. In vivo, in A431 xenograft, AF3485, administered sub-chronically, decreased tumor growth, an effect related to inhibition of EGFR signalling, and to tumor microvessel rarefaction. In fact, we observed a decrease of EGFR phosphorylation, and VEGF and FGF-2 expression in tumours explanted from treated mice. Conclusion Our work demonstrates that the pharmacological inhibition of mPGES-1 reduces squamous carcinoma growth by suppressing PGE2 mediated-EGFR signalling and by impairing tumor associated angiogenesis. These results underscore the potential of mPGES-1 inhibitors as agents capable of controlling tumor growth.
Bocci, Elena; Coletta, Isabella; Polenzani, Lorenzo; Mangano, Giorgina; Alisi, Maria Alessandra; Cazzolla, Nicola; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra
Restriction of tumor growth in mice by sodium-deficient diet.
Generalized malnutrition results in inhibition of tumorigenesis and tumor growth in experimental animal models. Neither the specific nutrient deficiency nor the mechanism has been definitely elucidated. We have shown previously that dietary sodium deprivation in rapidly growing rats retards protoplasmic growth. This effect was correlated to the extracellular fluid (ECF) volume expansion which is dependent on sodium accumulation. Since solid tumors are composed of a large quantity of ECF (which includes plasma volume) it was postulated that preventing the accumulation of new ECF by means of sodium restriction would influence tumor growth. The present study was designed to determine the effects of salt restriction on tumor growth and to relate these effects to ECF volume. Approximately 10(6) viable B16 melanoma cells were injected into C57BL/6 x DBA/2 F1 and C57 mice. A salt restricted diet (sodium less than 3 microeq/g) was provided ad libitum. The drinking solution was distilled water for the experimental group and 0.45% saline solution for the controls. There was a significant decrease in tumor growth rates during sodium restriction. The total body ECF volume increased when dietary sodium was supplied but did not change during salt restriction. Therefore, the only source for the ECF in the tumor mass was from nontumorous tissue. We conclude that during dietary sodium restriction solid tumor growth is retarded and can proceed only to the extent that ECF is released from cachectic body tissues. PMID:3370641
Fine, B P; Ponzio, N M; Denny, T N; Maher, E; Walters, T R
Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth.
Bmx, [corrected] also known as Etk, is a member of the Tec family of nonreceptor tyrosine kinases. Bmx is expressed mainly in arterial endothelia and in myeloid hematopoietic cells. Bmx regulates ischemia-mediated arteriogenesis and lymphangiogenesis, but its role in tumor angiogenesis is not known. In this study, we characterized the function of Bmx in tumor growth using both Bmx knockout and transgenic mice. Isogenic colon, lung, and melanoma tumor xenotransplants showed reductions in growth and tumor angiogenesis in Bmx gene-deleted ((-/-)) mice, whereas developmental angiogenesis was not affected. In addition, growth of transgenic pancreatic islet carcinomas and intestinal adenomas was also slower in Bmx(-/-) mice. Knockout mice showed high levels of Bmx expression in endothelial cells of tumor-associated and peritumoral arteries. Moreover, endothelial cells lacking Bmx showed impaired phosphorylation of extracellular signal-regulated kinase (Erk) upon VEGF stimulation, indicating that Bmx contributes to the transduction of vascular endothelial growth factor signals. In transgenic mice overexpressing Bmx in epidermal keratinocytes, tumors induced by a two-stage chemical skin carcinogenesis treatment showed increased growth and angiogenesis. Our findings therefore indicate that Bmx activity contributes to tumor angiogenesis and growth. PMID:22593188
Holopainen, Tanja; L�pez-Alpuche, Vanessa; Zheng, Wei; Heljasvaara, Ritva; Jones, Dennis; He, Yun; Tvorogov, Denis; D'Amico, Gabriela; Wiener, Zoltan; Andersson, Leif C; Pihlajaniemi, Taina; Min, Wang; Alitalo, Kari
Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model.
Lysosomal cysteine cathepsins contribute to proteolytic events promoting tumor growth and metastasis. Their enzymatic activity, however, is tightly regulated by endogenous inhibitors. To investigate the role of cathepsin inhibitor stefin B (Stfb) in mammary cancer, Stfb null mice were crossed with transgenic polyoma virus middle T oncogene (PyMT) breast cancer mice. We show that ablation of Stfb resulted in reduced size of mammary tumors but did not affect their rate of metastasis. Importantly, decrease in tumor growth was correlated with an increased incidence of dead cell islands detected in tumors of Stfb-deficient mice. Ex vivo analysis of primary PyMT tumor cells revealed no significant effects of ablation of Stfb expression on proliferation, angiogenesis, migration and spontaneous cell death as compared with control cells. However, upon treatment with the lysosomotropic agent Leu-Leu-OMe, cancer cells lacking Stfb exhibited a significantly higher sensitivity to apoptosis. Moreover, Stfb-ablated tumor cells were significantly more prone to cell death under increased oxidative stress. These results indicate an in vivo role for Stfb in protecting cancer cells by promoting their resistance to oxidative stress and to apoptosis induced through the lysosomal pathway. PMID:23955077
Butinar, M; Prebanda, M T; Rajkovi?, J; Jeri?, B; Stoka, V; Peters, C; Reinheckel, T; Kr�ger, A; Turk, V; Turk, B; Vasiljeva, O
Two Coordinated Mechanisms Underlie Tumor Necrosis Factor Alpha-Induced Immediate and Delayed I?B Kinase Activation
Tumor necrosis factor alpha (TNF-?)-induced NF-?B activation has been believed to depend on TRAF2- and cIAP1-mediated RIP1 ubiquitination. However, recent findings have challenged the notion that these proteins play essential roles in NF-?B activation. Here, by assessing the kinetics and amplitude of I?B kinase (IKK) activation, we report that TNF-?-induced immediate and robust activation of IKK requires K63-linked and linearly linked ubiquitination of RIP1 and that in the absence of RIP1 expression, TRAF2 and cIAP1 cooperatively induce delayed IKK activation by recruiting LUBAC to TNFR1. Knockdown of HOIP (a component of LUBAC) in RIP1-deficient cells completely impairs the recruitment and activation of IKK but does not affect K63-linked ubiquitination of TRAF2 and recruitment of TAK1 to TNFR1, suggesting that the K63-linked ubiquitin chain is not capable of recruiting IKK in vivo. We also demonstrate that TRAF2 and cIAP1 together, but not either one alone, directly catalyze linearly linked ubiquitination of RIP1. Importantly, in embryonic hepatocytes, TNF-? activates NF-?B through a RIP1-independent pathway. Thus, our findings clarify molecular details of this important signaling mechanism by providing evidence for the existence of two phases of IKK activation: the immediate phase, induced by TRAF2/cIAP1-mediated ubiquitination of RIP1, and the delayed phase, activated by TRAF2/cIAP1-dependent recruitment of LUBAC.
Blackwell, Ken; Zhang, Laiqun; Workman, Lauren M.; Ting, Adrian T.; Iwai, Kazuhiro
2'-Hydroxyflavanone inhibits prostate tumor growth through inactivation of AKT/STAT3 signaling and induction of cell apoptosis.
Although there have been advances in therapeutic regimes for metastatic castration-resistant prostate cancer (CRPC), these recent developments have not led to improved cure rates. Thus, more novel agents to prolong patient survival are desired. 2'-Hydroxyflavanone (2HF), a nontoxic natural flavonoid, has been shown to exhibit pleiotropic anticancer effects in many cancer types, including prostate cancer (PCa). However, the therapeutic effects of 2HF on tumor growth and its potential mechanisms in CRPC have not been completely elucidated. In the present study, utilizing three different metastatic and androgen-independent PCa cell models (PC-3, DU145 and C4-2), we found that 2HF treatment not only resulted in inhibition of cell proliferation and colony formation in�vitro, but also delayed subcutaneous tumor growth in�vivo. Mechanistically, besides its known inhibitory effects on aldo?keto reductase activity and de�novo androgen synthesis, 2HF also markedly suppressed AKT phosphorylation, signal transducer and activator of transcription-3 (STAT3) phosphorylation and transactivation subsequently regulating the expression of members of the BCL-2 family (i.e., Mcl-1, Bcl-2 and Bax) and modulating caspase-mediated cell apoptosis. Overall, this study revealed a novel mechanism for 2HF targeting metastatic CRPC, in which inactivation of AKT/STAT3 signaling led to cell apoptosis and growth inhibition. PMID:24859932
Wu, Kaijie; Ning, Zhongyun; Zhou, Jiancheng; Wang, Bin; Fan, Jinhai; Zhu, Jianning; Gao, Yang; Wang, Xinyang; Hsieh, Jer-Tsong; He, Dalin
A Zymomonas mobilis Mutant with Delayed Growth on High Glucose Concentrations
Exponentially growing cells of Zymomonas mobilis normally exhibit a lag period of up to 3 h when transferred from 0.11 M (2%) to 0.55 M (10%) glucose liquid medium. A mutant of Z. mobilis (CU1Rif2), fortuitously isolated, showed more than a 20-h lag period when grown under the same conditions, whereas on 0.55 M glucose solid medium, it failed to grow. The growth of CU1Rif2 on elevated concentrations of other fermentable (0.55 M sucrose or fructose) or nonfermentable (0.11 M glucose plus 0.44 M maltose or xylose) sugars appeared to be normal. Surprisingly, CU1Rif2 cells grew without any delay on 0.55 M glucose on which wild-type cells had been incubated for 3 h and removed at the beginning of their exponential phase. This apparent preconditioning was not observed with medium obtained from wild-type cells grown on 0.11 M glucose and supplemented to 0.55 M after removal of the wild-type cells. Undelayed growth of CU1Rif2 on 0.55 M glucose previously conditioned by the wild type was impaired by heating or protease treatment. It is suggested that in Z. mobilis, a diffusible proteinaceous heat-labile factor, transitionally not present in 0.55 M glucose CU1Rif2 cultures, triggers growth on 0.55 M glucose. Biochemical analysis of glucose uptake and glycolytic enzymes implied that glucose assimilation was not directly involved in the phenomenon. By use of a wild-type Z. mobilis genomic library, a 4.5-kb DNA fragment which complemented in low copy number the glucose-defective phenotype as well as glucokinase and glucose uptake of CU1Rif2 was isolated. This fragment carries a gene cluster consisting of four putative coding regions, encoding 167, 167, 145, and 220 amino acids with typical Z. mobilis codon usage, ?35 and ?10 promoter elements, and individual Shine-Dalgarno consensus sites. However, strong homologies were not detected in a BLAST2 (EMBL-Heidelberg) computer search with known protein sequences.
Douka, Eugenia; Koukkou, Anna Irini; Vartholomatos, Georgios; Frillingos, Stathis; Papamichael, Emmanuel M.; Drainas, Constantin
Oncolytic HSV and Erlotinib Inhibit Tumor Growth and Angiogenesis in a Novel Malignant Peripheral Nerve Sheath Tumor Xenograft Model
Malignant peripheral nerve sheath tumors (MPNSTs), driven in part by hyperactive Ras and epidermal growth factor receptor (EGFR) signaling, are often incurable. Testing of therapeutics for MPNST has been hampered by lack of adequate xenograft models. We previously documented that human MPNST cells are permissive for lytic infection by oncolytic herpes simplex viruses (oHSV). Herein we developed and characterized a
Yonatan Y Mahller; Sachin S Vaikunth; Mark A Currier; Shyra J Miller; Maria C Ripberger; Ya-Hsuan Hsu; Ruty Mehrian-Shai; Margaret H Collins; Timothy M Crombleholme; Nancy Ratner; Timothy P Cripe
Initiation of Liver Growth by Tumor Necrosis Factor: Deficient Liver Regeneration in Mice Lacking Type I Tumor Necrosis Factor Receptor
The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected
Yasuhiro Yamada; Irina Kirillova; Jacques J. Peschon; Nelson Fausto
Complete Inhibition of Rhabdomyosarcoma Xenograft Growth and Neovascularization Requires Blockade of Both Tumor and Host Vascular Endothelial Growth Factor
Growth of the human rhabdomyosarcoma A673 cell line in nude mice is substantially reduced but not completely suppressed after systemic administration of the antihuman vascular endothelial growth factor (VEGF) monoclonal antibody (Mab) A.4.6.1. Potentially, such escape might be attributable to incomplete local penetration of the antibody because of a diffusion barrier associated with tumor growth. Alterna- tively, it might reflect
Hans-Peter Gerber; Joe Kowalski; Daniel Sherman; David A. Eberhard; Napoleone Ferrara
tert-Butyl hydroperoxide, an organic peroxide, causes temporary delay in hair growth in a neonatal rat model
Summary tert-Butyl hydroperoxide (tBHP), an organic peroxide, has been shown to cause irreversible damage to keratinocytes in vitro with prolonged administration at high concentrations, and reversible damage with short-term administration at low concentrations. To investigate the effects of tBHP on keratinocytes in vivo, we analysed hair growth in tBHP-treated neonatal rats. Sprague�Dawley and Long�Evans rat pups were injected subcutaneously with tBHP or vehicle once daily for 6 days, and hair growth was monitored. The tBHP-treated rats had a significant delay in hair growth. However, this delay reversed within days, and the hair coats, including hair pigmentation, of tBHP-treated and sham-treated rats were indistinguishable 2 weeks later. Histological analysis and BrdU labelling of S phase cells confirmed the delay in hair-follicle growth and its reversal in tBHP-treated rats. Our results indicated that the changes incurred in hair follicles by short-term use of high-dose oxidants in vivo are temporary and reversible.
Wikramanayake, T. C.; Simon, J.; Mauro, L. M.; Perez, C. I.; Roberts, B.; Elgart, G.; Alvarez-Connelly, E.; Schachner, L. A.; Jimenez, J. J.
Phospholipase D (PLD) drives cell invasion, tumor growth and metastasis in a human breast cancer xenograph model.
Breast cancer is one of the most common malignancies in human females in the world. One protein that has elevated enzymatic lipase activity in breast cancers in vitro is phospholipase D (PLD), which is also involved in cell migration. We demonstrate that the PLD2 isoform, which was analyzed directly in the tumors, is crucial for cell invasion that contributes critically to the growth and development of breast tumors and lung metastases in vivo. We used three complementary strategies in a SCID mouse model and also addressed the underlying molecular mechanism. First, the PLD2 gene was silenced in highly metastatic, aggressive breast cancer cells (MDA-MB-231) with lentivirus-based short hairpin RNA, which were xenotransplanted in SCID mice. The resulting mouse primary mammary tumors were reduced in size (65%, P<0.05) and their onset delayed when compared with control tumors. Second, we stably overexpressed PLD2 in low-invasive breast cancer cells (MCF-7) with a biscistronic MIEG retroviral vector and observed that these cells were converted into a highly aggressive phenotype, as primary tumors that formed following xenotransplantation were larger, grew faster and developed lung metastases more readily. Third, we implanted osmotic pumps into SCID xenotransplanted mice that delivered two different small-molecule inhibitors of PLD activity (5-fluoro-2-indolyl des-chlorohalopemide and N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)ethyl]-2-naphthalenecarboxamide). These inhibitors led to significant (>70%, P<0.05) inhibition of primary tumor growth, metastatic axillary tumors and lung metastases. In order to define the underlying mechanism, we determined that the machinery of PLD-induced cell invasion is mediated by phosphatidic acid, Wiscott-Aldrich Syndrome protein, growth receptor-bound protein 2 and Rac2 signaling events that ultimately affect actin polymerization and cell invasion. In summary, this study shows for the first time that PLD2 has a central role in the development, metastasis and level of aggressiveness of breast cancer, raising the possibility that PLD2 could be used as a new therapeutic target. PMID:23752189
Henkels, K M; Boivin, G P; Dudley, E S; Berberich, S J; Gomez-Cambronero, J
The effect of interstitial pressure on tumor growth: coupling with the blood and lymphatic vascular systems.
The flow of interstitial fluid and the associated interstitial fluid pressure (IFP) in solid tumors and surrounding host tissues have been identified as critical elements in cancer growth and vascularization. Both experimental and theoretical studies have shown that tumors may present elevated IFP, which can be a formidable physical barrier for delivery of cell nutrients and small molecules into the tumor. Elevated IFP may also exacerbate gradients of biochemical signals such as angiogenic factors released by tumors into the surrounding tissues. These studies have helped to understand both biochemical signaling and treatment prognosis. Building upon previous work, here we develop a vascular tumor growth model by coupling a continuous growth model with a discrete angiogenesis model. We include fluid/oxygen extravasation as well as a continuous lymphatic field, and study the micro-environmental fluid dynamics and their effect on tumor growth by accounting for blood flow, transcapillary fluid flux, interstitial fluid flow, and lymphatic drainage. We thus elucidate further the non-trivial relationship between the key elements contributing to the effects of interstitial pressure in solid tumors. In particular, we study the effect of IFP on oxygen extravasation and show that small blood/lymphatic vessel resistance and collapse may contribute to lower transcapillary fluid/oxygen flux, thus decreasing the rate of tumor growth. We also investigate the effect of tumor vascular pathologies, including elevated vascular and interstitial hydraulic conductivities inside the tumor as well as diminished osmotic pressure differences, on the fluid flow across the tumor capillary bed, the lymphatic drainage, and the IFP. Our results reveal that elevated interstitial hydraulic conductivity together with poor lymphatic function is the root cause of the development of plateau profiles of the IFP in the tumor, which have been observed in experiments, and contributes to a more uniform distribution of oxygen, solid tumor pressure and a broad-based collapse of the tumor lymphatics. We also find that the rate that IFF is fluxed into the lymphatics and host tissue is largely controlled by an elevated vascular hydraulic conductivity in the tumor. We discuss the implications of these results on microenvironmental transport barriers, and the tumor invasive and metastatic potential. Our results suggest the possibility of developing strategies of targeting tumor cells based on the cues in the interstitial fluid. PMID:23220211
Wu, Min; Frieboes, Hermann B; McDougall, Steven R; Chaplain, Mark A J; Cristini, Vittorio; Lowengrub, John
Gompertz model with delays and treatment: mathematical analysis.
In this paper we study the delayed Gompertz model, as a typical model of tumor growth, with a term describing external interference that can reflect a treatment, e.g. chemotherapy. We mainly consider two types of delayed models, the one with the delay introduced in the per capita growth rate (we call it the single delayed model) and the other with the delay introduced in the net growth rate (the double delayed model). We focus on stability and possible stability switches with increasing delay for the positive steady state. Moreover, we study a Hopf bifurcation, including stability of arising periodic solutions for a constant treatment. The analytical results are extended by numerical simulations for a pharmacokinetic treatment function. PMID:23906135
Bodnar, Marek; Piotrowska, Monika Joanna; Fory?, Urszula
Platelet-Derived Growth Factor-BB Controls Epithelial Tumor Phenotype by Differential Growth Factor Regulation in Stromal Cells
Platelet-derived growth factor (PDGF) stimulates tumor growth and progression by affecting tumor and stromal cells. In the HaCaT skin carcinogenesis model, transfection of immortal nontumorigenic and PDGF-receptor-negative HaCaT keratinocytes with PDGF-B induced formation of benign tumors. Here, we present potential mechanisms underlying this tumorigenic conversion. In vivo, persistent PDGF-B expression induced enhanced tumor cell proliferation but only transiently stimulated stromal cell proliferation and angiogenesis. In vitro and in vivo studies identified fibroblasts as PDGF target cells essential for mediating transient angiogenesis and persistent epithelial hyperproliferation. In fibroblast cultures, long-term PDGF-BB treatment caused an initial up-regulation of vascular endothelial growth factor (VEGF)-A, followed by a drastic VEGF down-regulation and myofibroblast differentiation. Accordingly, in HaCaT/PDGF-B transplants, initially enhanced VEGF expression by stromal fibroblasts was subsequently reduced, followed by down-regulation of angiogenesis, myofibroblast accumulation, and vessel maturation. The PDGF-induced, persistently increased expression of the hepatocyte growth factor by fibroblasts in vitro and in vivo was most probably responsible for enhanced epithelial cell proliferation and benign tumor formation. Thus, by paracrine stimulation of the stroma, PDGF-BB induced epithelial hyperproliferation, thereby promoting tumorigenicity, whereas the time-limited activation of the stroma followed by stromal maturation provides a possible explanation for the benign tumor phenotype.
Lederle, Wiltrud; Stark, Hans-Jurgen; Skobe, Mihaela; Fusenig, Norbert E.; Mueller, Margareta M.
WT1-Mediated Growth Suppression of Wilms Tumor Cells Expressing a WT1 Splicing Variant
A human Wilms tumor cell line (RM1) was developed to test the tumor suppressor activity of WT1, a zinc finger transcription factor that is expressed in the developing human kidney and is mutationally inactivated in a subset of Wilms tumors. Transfection of each of four wild-type WT1 isoforms suppressed the growth of RM1 cells. The endogenous WT1 transcript in these
Daniel A. Haber; Seon Park; Shyamala Maheswaran; Christoph Englert; Gian G. Re; Debra J. Hazen-Martin; Donald A. Sens; A. Julian Garvin
Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival
We have shown recently that the hyaluronan receptor, CD44, and matrix metalloproteinase 9 (MMP-9) form a complex on the surface\\u000a of TA\\/St mouse mammary carcinoma cells that activates latent transforming growth factor-beta (TGF-?) and is required for tumor\\u000a invasion. Disruption of the CD44\\/MMP-9 complex by expression of soluble CD44 results in the loss of tumor invasiveness and\\u000a abrogates tumor cell
Qin Yu; Ivan Stamenkovic
A Generative Approach for Image-Based Modeling of Tumor Growth
Extensive imaging is routinely used in brain tumor patients to monitor the state of the disease and to evaluate therapeutic options. A large number of multi-modal and multi-temporal image volumes is acquired in standard clinical cases, requiring new approaches for comprehensive integration of information from different image sources and different time points. In this work we propose a joint generative model of tumor growth and of image observation that naturally handles multimodal and longitudinal data. We use the model for analyzing imaging data in patients with glioma. The tumor growth model is based on a reaction-diffusion framework. Model personalization relies only on a forward model for the growth process and on image likelihood. We take advantage of an adaptive sparse grid approximation for efficient inference via Markov Chain Monte Carlo sampling. The approach can be used for integrating information from different multi-modal imaging protocols and can easily be adapted to other tumor growth models.
Menze, Bjoern H.; Van Leemput, Koen; Honkela, Antti; Konukoglu, Ender; Weber, Marc-Andre; Ayache, Nicholas; Golland, Polina
Acetyl-11-Keto-?-Boswellic Acid Inhibits Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis
The role of angiogenesis in tumor growth and metastasis is well established. Identification of small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we demonstrated that acetyl-11-keto-?-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg of AKBA) after solid tumors reached about 100 mm3 (n=5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively and suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 kinase (KDR/Flk-1) with IC50 of 1.68 ?mol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mTOR, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.
Pang, Xiufeng; Yi, Zhengfang; Zhang, Xiaoli; Sung, Bokyung; Qu, Weijing; Lian, Xiaoyuan; Aggarwal, Bharat B.; Liu, Mingyao
Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis.
Analysis of patient tumors suggests that multiple MAP3 kinases (MAP3Ks) are critical for growth and metastasis of cancer cells. MAP3Ks selectively control the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase (JNK), p38 and ERK5 in response to receptor tyrosine kinases and GTPases. We used MDA-MB-231 cells because of their ability to metastasize from the breast fat pad to distant lymph nodes for an orthotopic xenograft model to screen the function of seven MAP3Ks in controlling tumor growth and metastasis. Stable short hairpin RNA (shRNA) knockdown was used to inhibit the expression of each of the seven MAP3Ks, which were selected for their differential regulation of the MAPK network. The screen identified two MAP3Ks, MEKK2 and MLK3, whose shRNA knockdown caused significant inhibition of both tumor growth and metastasis. Neither MEKK2 nor MLK3 have been previously shown to regulate tumor growth and metastasis in vivo. These results demonstrated that MAP3Ks, which differentially activate JNK, p38 and ERK5, are necessary for xenograft tumor growth and metastasis of MDA-MB-231 tumors. The requirement for MAP3Ks signaling through multiple MAPK pathways explains why several members of the MAPK network are activated in cancer. MEKK2 was required for epidermal growth factor receptor and Her2/Neu activation of ERK5, with ERK5 being required for metastasis. Loss of MLK3 expression increased mitotic infidelity and apoptosis in vitro. Knockdown of MEKK2 and MLK3 resulted in increased apoptosis in orthotopic xenografts relative to control tumors in mice, inhibiting both tumor growth and metastasis; MEKK2 and MLK3 represent untargeted kinases in tumor biology for potential therapeutic development. PMID:22139075
Cronan, M R; Nakamura, K; Johnson, N L; Granger, D A; Cuevas, B D; Wang, J-G; Mackman, N; Scott, J E; Dohlman, H G; Johnson, G L
V3 versican isoform expression has a dual role in human melanoma tumor growth and metastasis
Versican is a large chondroitin sulfate proteoglycan produced by several tumor cell types, including malignant melanoma, which exists as four different splice variants. The presence of versican in the extracellular matrix plays a role in tumor cell growth, adhesion and migration, which could be altered by altering the ratio between versican isoforms. We have previously shown that overexpression of the
Laia Miquel-Serra; Montserrat Serra; Daniel Hern�ndez; Clelia Domenzain; Mar�a Jos� Docampo; Rosa M Rabanal; In�s de Torres; Thomas N Wight; Angels Fabra; Anna Bassols
Expression of the antimicrobial peptide cathelicidin in myeloid cells is required for lung tumor growth.
Antimicrobial peptides, such as the cathelicidin LL-37/hCAP-18 and its mouse homolog cathelicidin-related antimicrobial peptide (CRAMP), are important effectors of the innate immune system with direct anti-bacterial activity. Cathelicidin is possibly involved in the regulation of tumor cell growth. The aim of this study was to characterize the role of cathelicidin expressed in non-tumorous cells in a preclinical mouse model of tumor growth. Wild-type and CRAMP-deficient animals were exposed to cigarette smoke (CS) and Lewis lung carcinoma cells were injected to initiate the growth of tumors in the lung. CS exposure significantly increased the proliferation of lung tumors in wild-type mice, but not in CRAMP-deficient mice. CS exposure induced the recruitment of myeloid cell into tumor tissue in a CRAMP-dependent manner. Mice lacking RelA/p65 specifically in myeloid cells showed impaired recruitment of CRAMP-positive cells into the lung. In vitro studies with human cells showed that LL-37/hCAP-18 in macrophages is induced by soluble factors derived from cancer cells. Taken together, these data indicate that cathelicidin expressed from myeloid cells promotes CS-induced lung tumor growth by further recruitment of inflammatory cells. The regulation of cathelicidin expression involves myeloid p65/RelA and soluble factor from tumor cells. PMID:23812430
Li, D; Beisswenger, C; Herr, C; Schmid, R M; Gallo, R L; Han, G; Zakharkina, T; Bals, R
Antigen forks: bispecific reagents that inhibit cell growth by binding selected pairs of tumor antigens
Bispecific antibodies of a new category, termed �antigen forks�, were constructed by crosslinking antibodies that recognized pairs of distinct tumor cell surface antigens. At concentrations of 1�100 nM, several such forks inhibited the growth of human tumor cell lines bearing both relevant antigens. The same cells were not inhibited by unconjugated component antibodies, and the active conjugates did not inhibit
David B. Ring; Sylvia T. Hsieh-Ma; Tim Shi; John Reeder
Estrogen Promotes Growth of Human Thyroid Tumor Cells by Different Molecular Mechanisms
Thyroid tumors are about 3 times more frequent in females than in males. Epidemiological studies suggest that the use of estrogens may contribute to the pathogenesis of thyroid tumors. In a very recent study a direct growth stimulatory effect of 17b-estradiol was dem- onstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors a and b
Increased primary tumor growth in mice null for ?3- or ?3/?5-integrins or selectins
Expression of ?v?3- or ?v?5-integrins and selectins is widespread on blood cells and endothelial cells. Here we report that human tumor cells injected s.c. into mice lacking ?3- or ?3/?5-integrins or various selectins show enhanced tumor growth compared with growth in control mice. There was increased angiogenesis in mice lacking ?3-integrins, but no difference in structure of the vessels was observed by histology or by staining for NG2 and smooth muscle actin in pericytes. Bone marrow transplants suggest that the absence of ?3-integrins on bone marrow-derived host cells contributes to the enhanced tumor growth in ?3-null mice, although few, if any, bone marrow-derived endothelial cells were found in the tumor vasculature. Tumor growth also was affected by bone marrow-derived cells in mice lacking any one or all three selectins, implicating both leukocyte and endothelial selectins in tumor suppression. Reduced infiltration of macrophages was observed in tumors grown in mice lacking either ?3-integrins or selectins. These results implicate cells of the innate immune system, macrophages or perhaps natural killer cells, in each case dependent on integrins and selectins, in tumor suppression.
Taverna, Daniela; Moher, Heather; Crowley, Denise; Borsig, Lubor; Varki, Ajit; Hynes, Richard O.
Pitt team finds protein that keeps balance between tumor cell growth and suppression
Using an approach that combines molecular biology, genetics, cell biology and physiology, and pathology, researchers at the University of Pittsburgh Cancer Institute (UPCI) and the University of Pittsburgh School of Medicine have identified a protein that governs a key molecule involved in orchestrating the balance between tumor growth and tumor suppression.
Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model
Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer cell growth, Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway and increased apoptosis. In a murine xenograft model of lung cancer, hematein inhibited tumor growth without significant toxicity to the mice tested. Molecular docking showed that hematein binds to CK2? in durable binding sites. Collectively, our results suggest that hematein is an allosteric inhibitor of protein kinase CK2 and has antitumor activity to lung cancer.
A Quantitative Theory of Solid Tumor Growth, Metabolic Rate and Vascularization
The relationships between cellular, structural and dynamical properties of tumors have traditionally been studied separately. Here, we construct a quantitative, predictive theory of solid tumor growth, metabolic rate, vascularization and necrosis that integrates the relationships between these properties. To accomplish this, we develop a comprehensive theory that describes the interface and integration of the tumor vascular network and resource supply with the cardiovascular system of the host. Our theory enables a quantitative understanding of how cells, tissues, and vascular networks act together across multiple scales by building on recent theoretical advances in modeling both healthy vasculature and the detailed processes of angiogenesis and tumor growth. The theory explicitly relates tumor vascularization and growth to metabolic rate, and yields extensive predictions for tumor properties, including growth rates, metabolic rates, degree of necrosis, blood flow rates and vessel sizes. Besides these quantitative predictions, we explain how growth rates depend on capillary density and metabolic rate, and why similar tumors grow slower and occur less frequently in larger animals, shedding light on Peto's paradox. Various implications for potential therapeutic strategies and further research are discussed.
Herman, Alexander B.; Savage, Van M.; West, Geoffrey B.
[The role of metalloproteinases in modification of extracellular matrix in invasive tumor growth, metastasis and angiogenesis].
Extracellular matrix metalloproteinases (MMPs) are a family of endopeptydases which recquire a zinc ion at their active site, for proteolityc activity. There are six members of the MMP family: matrilysins, collagenases, stromelysins, gelatinases, membrane MMPs and other MMPs. Activity of MMPs is regulated at the level of gene transcription, mRNA stability, zymogene proteolitic activation, inhibition of an active enzyme and MMP degradation. Tissue inhibitors of metalloproteinases (TIMPs) are main intracellular inhibitors of MMPs. Host cells can be stimulated by tumor cells to produce MMPs by secreted interleukins, interferons, growth factors and an extracellular matrix metalloproteinase inducer (EMMPRIN). MMPs are produced by tumor cells, fibroblasts, macrophages, mast cells, polimorphonuclear neutrophiles (PMNs) and endothelial cells (ECs). MMPs affect many stages of tumor development, facilitating its growth through promoting tumor cells proliferation, invasion and migration, new blood vessels formation and blocking tumor cells apoptosis. MMPs can promote tumor development in several ways. ECM degradation results in release of peptide growth factors. Growth factors linked with cell surface or binding proteins can also be liberated by MMPs. MMPs can indirectly regulate integrin signalling or cleave E-cadherins, facilitating cell migration. MMPs support metastasis inducing an epithelial to mesenchymal transition (EMT). MMP also support transendothelial migration. MMPs support angiogenesis by releasing pro-angiogenic factors and degrading ECM to support ECs migration. Cell surface growth factor receptors are also cleaved by MMPs, which results in inhibition of tumor development, so is release of anti-angiogenic factors from ECM.� PMID:23001203
Fink, Krzysztof; Boraty?ski, Janusz
Platelets Promote Tumor Growth and Metastasis via Direct Interaction between Aggrus/Podoplanin and CLEC-2
The platelet aggregation-inducing factor Aggrus, also known as podoplanin, is frequently upregulated in several types of tumors and enhances hematogenous metastasis by interacting with and activating the platelet receptor CLEC-2. Thus, Aggrus�CLEC-2 binding could be a therapeutic molecular mechanism for cancer therapy. We generated a new anti-human Aggrus monoclonal antibody, MS-1, that suppressed Aggrus�CLEC-2 binding, Aggrus-induced platelet aggregation, and Aggrus-mediated tumor metastasis. Interestingly, the MS-1 monoclonal antibody attenuated the growth of Aggrus-positive tumors in vivo. Moreover, the humanized chimeric MS-1 antibody, ChMS-1, also exhibited strong antitumor activity against Aggrus-positive lung squamous cell carcinoma xenografted into NOD-SCID mice compromising antibody-dependent cellular cytotoxic and complement-dependent cytotoxic activities. Because Aggrus knockdown suppressed platelet-induced proliferation in vitro and tumor growth of the lung squamous cell carcinoma in vivo, Aggrus may be involved in not only tumor metastasis but also tumor growth by promoting platelet-tumor interaction, platelet activation, and secretion of platelet-derived factors in vivo. Our results indicate that molecular target drugs inhibiting specific platelet�tumor interactions can be developed as antitumor drugs that suppress both metastasis and proliferation of tumors such as lung squamous cell carcinoma.
Takagi, Satoshi; Sato, Shigeo; Oh-hara, Tomoko; Takami, Miho; Koike, Sumie; Mishima, Yuji; Hatake, Kiyohiko; Fujita, Naoya
Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2.
The platelet aggregation-inducing factor Aggrus, also known as podoplanin, is frequently upregulated in several types of tumors and enhances hematogenous metastasis by interacting with and activating the platelet receptor CLEC-2. Thus, Aggrus-CLEC-2 binding could be a therapeutic molecular mechanism for cancer therapy. We generated a new anti-human Aggrus monoclonal antibody, MS-1, that suppressed Aggrus-CLEC-2 binding, Aggrus-induced platelet aggregation, and Aggrus-mediated tumor metastasis. Interestingly, the MS-1 monoclonal antibody attenuated the growth of Aggrus-positive tumors in vivo. Moreover, the humanized chimeric MS-1 antibody, ChMS-1, also exhibited strong antitumor activity against Aggrus-positive lung squamous cell carcinoma xenografted into NOD-SCID mice compromising antibody-dependent cellular cytotoxic and complement-dependent cytotoxic activities. Because Aggrus knockdown suppressed platelet-induced proliferation in vitro and tumor growth of the lung squamous cell carcinoma in vivo, Aggrus may be involved in not only tumor metastasis but also tumor growth by promoting platelet-tumor interaction, platelet activation, and secretion of platelet-derived factors in vivo. Our results indicate that molecular target drugs inhibiting specific platelet-tumor interactions can be developed as antitumor drugs that suppress both metastasis and proliferation of tumors such as lung squamous cell carcinoma. PMID:23991201
Takagi, Satoshi; Sato, Shigeo; Oh-hara, Tomoko; Takami, Miho; Koike, Sumie; Mishima, Yuji; Hatake, Kiyohiko; Fujita, Naoya
Mast Cells in Tumor Growth: Angiogenesis, Tissue Remodeling and Immune-modulation
Summary There is a growing acceptance that tumor-infiltrating myeloid cells play an active role in tumor growth and mast cells are one of the earliest cell types to infiltrate developing tumors. Mast cells accumulate at the boundary between healthy tissues and malignancies and are often found in close association with blood vessels within the tumor microenvironment. They express many pro-angiogenic compounds, and may play an early role in angiogenesis within developing tumors. Mast cells also remodel extracellular matrix during wound healing, and this function is subverted in tumor growth, promoting tumor spread and metastasis. In addition, mast cells modulate immune responses by dampening immune rejection or directing immune cell recruitment, depending on local stimuli. In this review, we focus on key roles for mast cells in angiogenesis, tissue remodeling and immune modulation and highlight recent findings on the integral role that mast cells play in tumor growth. New findings suggest that mast cells may serve as a novel therapeutic target for cancer treatment and that inhibiting mast cell function may lead to tumor regression.
Maltby, Steven; Khazaie, Khashayarsha; McNagny, Kelly M.
Effects of Cordyceps militaris extract on angiogenesis and tumor growth1
3 R&D Lab of Bulrolife Co, Ltd, Daejeon, Korea ABSTRACT AIM: To evaluate the effects of Cordyceps militaris extract (CME) on angiogenesis and tumor growth. METHODS: Human umbilical vein endothelial cells (HUVEC), HT1080, and B16-F10 cells were used. DNA fragment, angio- genic related gene expressions (MMPs, bFGF, VEGF, etc), capillary tube formation, wound healing in vitro, tumor growth in vivo
Hwa-seung YOO; Jang-woo SHIN; Jung-hyo CHO; Yeon-weol LEE; Sang-yong PARK; Chong-kwan CHO
Antisense suppression of deoxyhypusine synthase in tomato delays fruit softening and alters growth and development.
The effects of suppressing deoxyhypusine synthase (DHS) have been examined in tomato (Solanum lycopersicum cv UCT5). DHS mediates the first of two sequential enzymatic reactions that activate eukaryotic translation initiation factor-5A (eIF-5A) by converting a conserved Lys to the unusual amino acid, deoxyhypusine. DHS protein levels were suppressed in transgenic plants by expressing the 3'-untranslated region of tomato DHS under regulation of the constitutive cauliflower mosaic virus promoter. Fruit from the transgenic plants ripened normally, but exhibited delayed postharvest softening and senescence that correlated with suppression of DHS protein levels. Northern-blot analysis indicated that all four gene family members of tomato eIF-5A are expressed in fruit, and that three are up-regulated in parallel with enhancement of DHS mRNA as the fruit begin to senesce and soften. Transgenic plants in which DHS was more strongly suppressed were male sterile, did not produce fruit, and had larger, thicker leaves with enhanced levels of chlorophyll. The activity of PSII was 2 to 3 times higher in these transgenic leaves than in corresponding leaves of wild-type plants, and there was also enhanced deposition of starch in the stems. The data collectively indicate that suppression of DHS has pleiotropic effects on growth and development of tomato. This may, in turn, reflect the fact that there is a single DHS gene in tomato and that its cognate protein is involved in the activation of four distinct isoforms of eIF-5A. PMID:15951486
Wang, Tzann-Wei; Zhang, Chun-Guang; Wu, Wendy; Nowack, Linda M; Madey, Ewa; Thompson, John E
Angiogenesis-independent tumor growth mediated by stem-like cancer cells
In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors.
Sakariassen, Per ?.; Prestegarden, Lars; Wang, Jian; Skaftnesmo, Kai-Ove; Mahesparan, Rupavathana; Molthoff, Carla; Sminia, Peter; Sundlisaeter, Eirik; Misra, Anjan; Tysnes, Berit B?lge; Chekenya, Martha; Peters, Hans; Lende, Gabriel; Kalland, Karl Henning; ?yan, Anne M.; Petersen, Kjell; Jonassen, Inge; van der Kogel, Albert; Feuerstein, Burt G.; Terzis, A. Jorge A.; Bjerkvig, Rolf; Enger, Per ?yvind
Angiogenesis-independent tumor growth mediated by stem-like cancer cells.
In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors. PMID:17056721
Sakariassen, Per �; Prestegarden, Lars; Wang, Jian; Skaftnesmo, Kai-Ove; Mahesparan, Rupavathana; Molthoff, Carla; Sminia, Peter; Sundlisaeter, Eirik; Misra, Anjan; Tysnes, Berit B�lge; Chekenya, Martha; Peters, Hans; Lende, Gabriel; Kalland, Karl Henning; �yan, Anne M; Petersen, Kjell; Jonassen, Inge; van der Kogel, Albert; Feuerstein, Burt G; Terzis, A Jorge A; Bjerkvig, Rolf; Enger, Per �yvind
Preventing Growth of Brain Tumors by Creating a Zone of Resistance
Glioblastoma multiforme (GBM) is a devastating form of brain cancer for which there is no effective treatment. Here, we report a novel approach to brain tumor therapy through genetic modification of normal brain cells to block tumor growth and effect tumor regression. Previous studies have focused on the use of vector-based gene therapy for GBM by direct intratumoral injection with expression of therapeutic proteins by tumor cells themselves. However, as antitumor proteins are generally lethal to tumor cells, the therapeutic reservoir is rapidly depleted, allowing escape of residual tumor cells. Moreover, it has been difficult to achieve consistent transduction of these highly heterogeneous tumors. In our studies, we found that transduction of normal cells in the brain with an adeno-associated virus (AAV) vector encoding interferon-? (IFN-?) was sufficient to completely prevent tumor growth in orthotopic xenograft models of GBM, even in the contralateral hemisphere. In addition, complete eradication of established tumors was achieved through expression of IFN-? by neurons using a neuronal-restricted promoter. To our knowledge this is the first direct demonstration of the efficacy of targeting gene delivery exclusively to normal brain cells for brain tumor therapy.
Maguire, Casey A; Meijer, Dimphna H; LeRoy, Stanley G; Tierney, Laryssa A; Broekman, Marike LD; Costa, Fabricio F; Breakefield, Xandra O; Stemmer-Rachamimov, Anat; Sena-Esteves, Miguel
Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience.
Because interleukin-10 (IL-10) has potent immunosuppressive and anti-inflammatory properties and is produced by some cancers, including melanoma, we hypothesized that its production by tumor cells may contribute to the escape from immune surveillance. To test this hypothesis, we transfected human A375P melanoma cells that do not express IL-10 with the murine IL-10 gene and subsequently analyzed for changes in tumor growth and metastasis in nude mice. Surprisingly, IL-10 gene transfer resulted in a loss of metastasis and significant inhibition of tumor growth. In addition, the growth of other murine or human melanoma cells was also inhibited when they were admixed with IL-10-transfected cells before injection into nude mice. We provide evidence that IL-10 exerts its antitumor and antimetastatic activity by inhibiting angiogenesis in vivo. The in vivo decrease in neovascularization found in IL-10-secreting tumors is most likely due to the ability of IL-10 to downregulate the synthesis of vascular endothelial growth factor (VEGF), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and matrix metalloproteinase-9 (MMP-9) in tumor-associated macrophages. Other studies have shown that IL-10 inhibits tumor metastasis through a natural killer (NK) cell-dependent mechanism. The inhibitory effects of IL-10 on tumor growth and metastasis were also demonstrated in other tumor models, including breast cancers. Furthermore, administration of rIL-10 into mice resulted in inhibition of tumor metastasis. Because IL-10 has little toxicity when given systemically to human volunteers, its efficacy as an antimetastatic agent should be further explored, both as an independent and in combination with other inhibitors of neovascularization. PMID:10454339
Huang, S; Ullrich, S E; Bar-Eli, M
Mesenchymal stem cells promote growth and angiogenesis of tumors in mice.
Though the early integration of mesenchymal stem cells (MSCs) into tumor-associated stroma of cancer has been demonstrated, the functional contributions and underlying mechanisms of these cells to tumor growth and angiogenesis remain to be clarified. Using a xenograft model, human colorectal cancer cells, MSCs, and their cell mixture were introduced to a subcutaneous site of immunodeficient mice. The tumor growth rate and angiogenesis of each transplantation was then compared. We demonstrate that a variety of colorectal cancer cells, when mixed with otherwise non-tumorigenic MSCs, increase the tumor growth rate and angiogenesis more than that when mixed with carcinoma-associated fibroblasts or normal colonic fibroblasts. The secretion of interleukin-6 (IL-6) from MSCs increases the secretion of endothelin-1 (ET-1) in cancer cells, which induces the activation of Akt and ERK in endothelial cells, thereby enhancing their capacities for recruitment and angiogenesis to tumor. The IL-6/ET-1/Akt or ERK pathway of tumor-stroma interaction can be targeted by an antibody against IL-6 or Lentiviral-mediated RNAi against IL-6 in MSCs, by inhibition or knockdown of ET-1 in cancer cells, or by inhibition of ERK and Akt in host endothelial cells. These demonstrate that attempts to interrupt the interaction of MSCs and cancer cells help to abrogate angiogenesis and inhibit tumor growth in tumors formed by cancer cells admixed with MSCs. These data demonstrate that the tumor microenvironment, namely, MSCs-secreted IL-6, may enrich the proangiognic factors secreted by cancer cells to increase angiogenesis and tumor growth and that targeting this interaction may lead to novel therapeutic and preventive strategies. PMID:23085755
Huang, W-H; Chang, M-C; Tsai, K-S; Hung, M-C; Chen, H-L; Hung, S-C
Enhancement of tumor associated antigen expression during the regression phase of xenogenized tumor cell growth in vivo.
Rat fibrosarcoma cells infected with Friend leukemia virus (FV-KMT-17) grow for a short time and then regress spontaneously in syngeneic hosts. This regression was caused by immunological mechanisms, because the tumor cells were renogenized. In this study, we have tried to find out whether tumor-associated antigen (TAA) expression in these xenogenized tumor cells can be modulated by xenogenization. FV-KMT-17 cells (1 x 10(7)), which were subcutaneously transplanted into ten rats, spontaneously regressed after temporary growth. All rats which rejected FV-KMT-17 cells showed strong resistance to rechallenge with KMT-17 (1 x 10(6)) cells. To reveal the chronological modulation of TAA and virus-associated antigen (VAA), a single-cell suspension was obtained from the subcutaneous tumors and expression of these antigens was chronologically measured. TAA, termed CE7 antigen, was examined by anti-CE7 monoclonal antibody (MoAb) and VAA was examined by anti-FK1 MoAb which recognizes the FV env gene product (gp 70). Expression of VAA was not modulated through either the progression or the regression phase, but expression of TAA was strongly enhanced in the regression phase. These results show that enhancement of TAA expression occurs during the regression phase of FV-KMT-17 growth in vivo and that TAA-expressing cells may stimulate anti-tumor immunity, resulting in acquisition of resistance against parental KMT-17 cells. PMID:9216677
Shibata, T; Micallef, M; Chiba, I; Arisue, M; Hosokawa, M; Okada, F; Takeichi, N; Kobayashi, H
The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors.
Glioblastoma multiforme (GBM) is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M) is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer. PMID:24319475
Lin, Yu-Ling; Lai, Wen-Lin; Harn, Horng-Jyh; Hung, Pei-Hsiu; Hsieh, Ming-Chang; Chang, Kai-Fu; Huang, Xiao-Fan; Liao, Kuang-Wen; Lee, Ming-Shih; Tsai, Nu-Man
The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors
Glioblastoma multiforme (GBM) is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M) is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer.
Lai, Wen-Lin; Harn, Horng-jyh; Hung, Pei-Hsiu; Hsieh, Ming-Chang; Chang, Kai-Fu; Huang, Xiao-Fan; Liao, Kuang-Wen; Lee, Ming-Shih; Tsai, Nu-Man
Solid tumor models for the assessment of different treatment modalities: I. Radiation-induced changes in growth rate characteristics of a solid tumor model.
A computer program has been developed to quantitatively evaluate changes in tumor growth rates of a solid tumor model (hepatoma 3924A) after a series of radiation doses from 375 R to 3750 R. The computer-derived growth curves are simulated from the volumes of the individual tumors rather than from the mean tumor volume at any specific time point after treatment. The ability to generate data from a family of tumor growth curves permits a more precise evaluation of therapeutic effects on tumors than can be obtained with conventional methods. The quantitative determination of equivalent amounts of radiation needed to produce comparable 5-fluorouracil-induced changes in tumor growth rate has been made. The ability to determine quantitatively radiotherapeutic and chemotherapy equivalents on these solid tumor models has direct implications in regard to our effort to improve the treatment of cancer. At present no specific solid tumor or groups of solid tumors have provided all of the necessary information for clinical utilization in therapeutic scheduling of different forms of cancer treatment. Since solid tumors comprise the majority of human cancer, one of the primary objectives of these studies has been the establishment of a solid tumor model that could serve both as a system for devising improved therapeutic scheduling and for a better understanding of solid tumors.
Looney, W B; Trefil, J S; Schaffner, J C; Kovacs, C J; Hopkins, H A
Caspase 3 promotes surviving melanoma tumor cell growth after cytotoxic therapy.
Metastatic melanoma often relapses despite cytotoxic treatment, and hence the understanding of melanoma tumor repopulation is crucial for improving our current therapies. In this study, we aim to define the role of caspase 3 in melanoma tumor growth after cytotoxic therapy. We examined a paradigm-changing hypothesis that dying melanoma cells undergoing apoptosis during cytotoxic treatment activate paracrine signaling events that promote the growth of surviving tumor cells. We propose that caspase 3 has a key role in the initiation of the release of signals from dying cells to stimulate melanoma tumor growth. We created a model for tumor cell repopulation in which a small number of luciferase-labeled, untreated melanoma cells are seeded onto a layer of a larger number of unlabeled, lethally treated melanoma cells. We found that dying melanoma cells significantly stimulate the growth of living melanoma cells in vitro and in vivo. Furthermore, we observed that caspase 3 gene knockdown attenuated the growth-stimulating effect of irradiated, dying cells on living melanoma cell growth. Finally, we showed that caspase 3-mediated dying melanoma cell stimulation of living cell growth involves secreted prostaglandin E2 (PGE2). Our study therefore suggests a counterintuitive strategy to inhibit caspase 3 for therapeutic gain in melanoma treatment. PMID:24434746
Donato, Anne L; Huang, Qian; Liu, Xinjian; Li, Fang; Zimmerman, Mary A; Li, Chuan-Yuan
Origin of the vasculature supporting growth of primary patient tumor xenografts
Background Studies of primary patient tumor xenografts grown in immunodeficient mice have shown that these tumors histologically and genetically closely resemble the original tumors. These patient xenograft models are becoming widely used for therapeutic efficacy studies. Because many therapies are directed at tumor stromal components and because the tumor microenvironment also is known to influence the response of a tumor to therapy, it is important to understand the nature of the stroma and, in particular, the vascular supply of patient xenografts. Methods Patient tumor xenografts were established by implanting undisrupted pieces of patient tumors in SCID mice. For this study, formalin fixed, paraffin embedded specimens from several types of solid tumors were selected and, using species-specific antibodies which react with formalin fixed antigens, we analyzed the species origin of the stroma and blood vessels that supported tumor growth in these models. Additionally, we investigated the kinetics of the vascularization process in a colon tumor and a mesothelioma xenograft. In mice bearing a head and neck xenograft, a perfusion study was performed to compare the functionality of the human and mouse tumor vessels. Results In patient tumors which successfully engrafted, the human stroma and vessels which were engrafted as part of the original tumor did not survive and were no longer detectable at the time of first passage (15�25 weeks). Uniformly, the stroma and vessels supporting the growth of these tumors were of murine origin. The results of the kinetic studies showed that the loss of the human vessels and vascularization by host vessels occurred more rapidly in a colon tumor (by 3 weeks) than in a mesothelioma (by 9 weeks). Finally, the perfusion studies revealed that while mouse vessels in the periphery of the tumor were perfused, those in the central regions were rarely perfused. No vessels of human origin were detected in this model. Conclusions In the tumors we investigated, we found no evidence that the human stromal cells and vessels contained in the original implant either survived or contributed in any substantive way to the growth of these xenografts.
Vital microscopic analysis of polymeric micelle extravasation from tumor vessels: macromolecular delivery according to tumor vascular growth stage.
Particles larger than a specific size have been thought to extravasate from tumor vessels but not from normal vessels. Therefore, various nanoparticles incorporating anticancer drugs have been developed to realize selective drug delivery to solid tumors. However, it is not yet clear whether nanoparticles extravasate readily from all tumor vessels including vessels of microtumors. To answer this question, we synthesized new polymeric micelles labeled with fluorescein isothiocyanate (FITC) and injected them into the tail vein of rats with implanted skinfold transparent chambers. We also analyzed, by means of time-lapse vital microscopy with image analysis, extravasation of FITC micelles from tumor vessels at different stages of growth of Yoshida ascites sarcoma LY80. Polymeric micelles readily leaked from vessels at the interface between normal and tumor tissues and those at the interface between tumor tissues and necrotic areas. The micelles showed negligible extravasation, however, from the vascular network of microtumors less than 1 mm in diameter and did not accumulate in the microtumor. Our results suggest that we must develop a novel therapeutic strategy that can deliver sufficient nanomedicine to microtumors. PMID:19544373
Hori, Katsuyoshi; Nishihara, Masamichi; Yokoyama, Masayuki
IgG2a Monoclonal Antibodies Inhibit Human Tumor Growth through Interaction with Effector Cells
NASA Astrophysics Data System (ADS)
Monoclonal antibodies of IgG2a isotype specifically inhibited growth of human tumors in nude mice. Twentythree monoclonal antibodies of other isotypes showed no tumoricidal reactivity. Complement depletion of nude mice had no effect on tumor suppression by monoclonal antibody. The role of T and killer cells as mediators of the monoclonal antibody effect in nude mice was virtually excluded. On the other hand, macrophages were strongly incriminated as effector cells because silica treatment of nude mice abolished the tumoricidal effect of monoclonal antibody. IgG2a monoclonal antibody-dependent macrophagemediated cytotoxicity assays with human tumor cells in culture resulted in specific lysis of tumor cells.
Herlyn, Dorothee; Koprowski, Hilary
PPAR? agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition
Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)? deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPAR? would promote tumor growth. Surprisingly, the PPAR? agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPAR?-deficient tumors were still susceptible to fenofibrate, absence of PPAR? in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPAR? as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPAR? agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPAR? agonists in cancer treatment, alone and in combination with other therapies.
Panigrahy, Dipak; Kaipainen, Arja; Huang, Sui; Butterfield, Catherine E.; Barnes, Carmen M.; Fannon, Michael; Laforme, Andrea M.; Chaponis, Deviney M.; Folkman, Judah; Kieran, Mark W.
Growth inhibition of ovarian tumor-initiating cells by niclosamide.
A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy. PMID:22576131
Yo, Yi-Te; Lin, Ya-Wen; Wang, Yu-Chi; Balch, Curt; Huang, Rui-Lan; Chan, Michael W Y; Sytwu, Huey-Kang; Chen, Chi-Kuan; Chang, Cheng-Chang; Nephew, Kenneth P; Huang, Tim; Yu, Mu-Hsien; Lai, Hung-Cheng
Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of tumor growth and tumor angiogenesis of mouse ehrlich ascites tumor in vivo.
A series of novel 1-benzhydryl-sulfonyl-piperazine derivatives 3(a-e) were synthesized by nucleophilic substitution reaction of 1-benzhydryl-piperazine with different sulfonyl chlorides and were characterized by 1H NMR, LC/MS, FTIR and elemental analysis. In the present study, the compounds 3(a-e) exhibited in vivo inhibition of Ehrlich ascites tumor (EAT) cell growth and increased the Median Survival Time (MST) and %ILS of EAT bearing mice. Further treatment of derivatives in vivo resulted in reduction of EAT cell number and ascites formation. The efficacy of the derivatives to inhibit the angiogenesis in vivo was evaluated in tumor bearing mice peritoneum and chorio allantoic membrane (CAM) model. The compounds suppressed the blood vessel formation in vivo in mice peritoneum and in CAM. Among the compounds studied, 3e demonstrated highest tumor inhibitory and anti-angiogenic effects against mouse tumor. However, this phenomenon needs detailed investigation. PMID:18782043
Kumar, C S Ananda; Chandru, H; Sharada, A C; Thimmegowda, N R; Prasad, S B Benaka; Kumar, M Karuna; Rangappa, K S
MHC-mismatched mice liver transplantation promotes tumor growth in liver graft.
Liver transplantation is a final therapeutic option for treatment of hepatic malignancies, but local recurrence remains high after surgery. However, the underlying mechanisms of local tumor recurrence are still unknown. We speculated that immunological status of transplanted liver may contribute to the progress of tumor development. CT-26 tumor cells are injected into graft after allogeneic or syngeneic liver transplantation. The growth pattern of tumor and the co-relationship of regulatory T cell and effector T cells in liver graft were observed and investigated at 3d, 6d, 9d and 15d post-transplantation. The Hepatic Replacement Area of tumor in allogeneic grafts was significantly larger than that in syngeneic grafts. The activation of tumor growth in allografts was due to the dysfunction of effector T cells mediated by regulatory T cells in liver graft. Using nude mice model, we further confirmed that regulatory T cells from allograft significantly weaken the function of effector T cells in vivo. Our data has showed that MHC-mismatched mice liver transplantation can promote tumor growth in liver graft. For the first time, we demonstrated that susceptibility to tumor development in liver graft is due to the down-regulation of effector T cells' function mediated by the regulatory T cells. PMID:24880081
Yan, Sheng; Ding, Yuan; Tian, Yang; Lu, Zhongjie; Wang, Yan; Zhang, Qiyi; Ye, Yufu; Zhou, Lin; Xie, Haiyang; Chen, Hui; Zheng, Minghao; Zheng, Shusen
AMPK is a negative regulator of the Warburg Effect and suppresses tumor growth in vivo
Summary AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells, and suppresses tumor growth in vivo. Genetic ablation of the ?1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPK? in both transformed and non-transformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1? (HIF-1?), as silencing HIF-1? reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPK? signaling. Together our findings suggest that AMPK activity opposes tumor development, and its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.
Faubert, Brandon; Boily, Gino; Izreig, Said; Griss, Takla; Samborska, Bozena; Dong, Zhifeng; Dupuy, Fanny; Chambers, Christopher; Fuerth, Benjamin J.; Viollet, Benoit; Mamer, Orval A.; Avizonis, Daina; DeBerardinis, Ralph J.; Siegel, Peter M.; Jones, Russell G.
A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors.
The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors. PMID:14595012
Rubin, Joshua B; Kung, Andrew L; Klein, Robyn S; Chan, Jennifer A; Sun, YanPing; Schmidt, Karl; Kieran, Mark W; Luster, Andrew D; Segal, Rosalind A
A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors
The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.
Rubin, Joshua B.; Kung, Andrew L.; Klein, Robyn S.; Chan, Jennifer A.; Sun, YanPing; Schmidt, Karl; Kieran, Mark W.; Luster, Andrew D.; Segal, Rosalind A.
Tumor-host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas.
The host-tumor interaction may play an important role in determining tumor progress. Recent studies have shown that this interaction can be influenced by the release of soluble factors by tumor cells and tumor-infiltrating lymphocytes (TIL). The aim of our study is to characterize the nature of cytokines and growth factors and their relationship to the cellular infiltrates in 16 patients with ovarian cancer using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Total RNA from 20 malignant and 10 benign specimens were used to assay for expression of 12 cytokines. Additionally, monoclonal antibodies (MAbs) were used to detect T cells, CD4+ helper and CD8+ cytotoxic/suppressor T-cell subtypes, B cells, and macrophages. Our results showed the expression of transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 19, 17, and 10 malignant specimens, P < .001, .001, and .05, respectively. Other cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta/LT, IL-2, and IL-6 were expressed in a few cases, and IL-1alpha and IL-4 expression were not detected. The benign samples did not express IL-10, but GM-CSF, TGF-beta1, and IL-8 were expressed in one, one, and four specimens, respectively. Interestingly, in four cases in which samples from the primary and relapse tumors were available for analysis, the tumors in relapse showed a significant increase for TGF-beta1 (P < .05) and a decreased trend in IL-10 mRNA levels. The source of these factors was tumor cells as detected immunohistochemically. This combined alteration of TGF-beta1 and IL-10 was associated with a significant reduction in number of TIL in general, and CD8+ and macrophages in particular (P = .036 and .049, respectively). Our findings suggest the important role of certain soluble factors in the complex process of tumor progression. Furthermore, understanding the tumor-host relationship and the factors influencing the interaction may be helpful in developing effective and innovative treatment methods. PMID:9042797
Merogi, A J; Marrogi, A J; Ramesh, R; Robinson, W R; Fermin, C D; Freeman, S M
Macrophage inflammatory protein-2 contributes to liver resection-induced acceleration of hepatic metastatic tumor growth
AIM: To study the role of macrophage inflammatory protein (MIP)-2 in liver resection-induced acceleration of tumor growth in a mouse model of hepatic metastasis. METHODS: After a 50% hepatectomy, 1�105 CT26.WT cells were implanted into the left liver lobe of syngeneic balb/c mice (PHx). Additional animals were treated with a monoclonal antibody (MAB452) neutralizing MIP-2 (PHx+mAB). Non-resected and non-mAB-treated mice (Con) served as controls. After 7 d, tumor angiogenesis and microcirculation as well as cell proliferation, tumor growth, and CXCR-2 expression were analyzed using intravital fluorescence microscopy, histology, immunohistochemistry, and flow cytometry. RESULTS: Partial hepatectomy increased (P?0.05) the expression of the MIP-2 receptor CXCR-2 on tumor cells when compared with non-resected controls, and markedly accelerated (P?0.05) angiogenesis and metastatic tumor growth. Neutralization of MIP-2 by MAB452 treatment significantly (P?0.05) depressed CXCR-2 expression. Further, the blockade of MIP-2 reduced the angiogenic response (P?0.05) and inhibited tumor growth (P?0.05). Of interest, liver resection-induced hepatocyte proliferation was not effected by anti-MIP-2 treatment. CONCLUSION: MIP-2 significantly contributes to liver resection-induced acceleration of colorectal CT26.WT hepatic metastasis growth.
Kollmar, Otto; Menger, Michael D; Schilling, Martin K
Expression of P2X7 receptor increases in vivo tumor growth.
The P2X7 receptor is an ATP-gated ion channel known for its cytotoxic activity. However, recent evidence suggests a role for P2X7 in cell proliferation. Here, we found that P2X7 exhibits significant growth-promoting effects in vivo. Human embryonic kidney cells expressing P2X7 exhibited a more tumorigenic and anaplastic phenotype than control cells in vivo, and the growth rate and size of these tumors were significantly reduced by intratumoral injection of the P2X7 inhibitor-oxidized ATP. The accelerated growth of P2X7-expressing tumors was characterized by increased proliferation, reduced apoptosis, and a high level of activated transcription factor NFATc1. These tumors also showed a more developed vascular network than control tumors and secreted elevated amounts of VEGF. The growth and neoangiogenesis of P2X7-expressing tumors was blocked by intratumoral injection of the VEGF-blocking antibody Avastin (bevacizumab), pharmacologic P2X7 blockade, or P2X7 silencing in vivo. Immunohistochemistry revealed strong P2X7 positivity in several human cancers. Together, our findings provide direct evidence that P2X7 promotes tumor growth in vivo. PMID:22505653
Adinolfi, Elena; Raffaghello, Lizzia; Giuliani, Anna Lisa; Cavazzini, Luigi; Capece, Marina; Chiozzi, Paola; Bianchi, Giovanna; Kroemer, Guido; Pistoia, Vito; Di Virgilio, Francesco
Polyphenols in brewed green tea inhibit prostate tumor xenograft growth by localizing to the tumor and decreasing oxidative stress and angiogenesis
It has been demonstrated in various animal models that the oral administration of green tea (GT) extracts in drinking water can inhibit tumor growth, but the effects of brewed GT on factors promoting tumor growth, including oxidant damage of DNA and protein, angiogenesis, and DNA methylation, have not been tested in an animal model. To explore these potential mechanisms, brewed GT was administered instead of drinking water to male severe combined immunodeficiency (SCID) mice with androgen-dependent human LAPC4 prostate cancer cell subcutaneous xenografts. Tumor volume was decreased significantly in mice consuming GT, and tumor size was significantly correlated with GT polyphenol (GTP) content in tumor tissue. There was a significant reduction in hypoxia-inducible factor 1-alpha and vascular endothelial growth factor protein expression. GT consumption significantly reduced oxidative DNA and protein damage in tumor tissue as determined by 8-hydroxydeoxyguanosine/deoxyguanosine ratio and protein carbonyl assay, respectively. Methylation is known to inhibit antioxidative enzymes such as glutathione S-transferase pi (GSTp1) to permit reactive oxygen species promotion of tumor growth. GT inhibited tumor 5-cytosine DNA methyltransferase 1 (DNMT1) mRNA and protein expression significantly, which may contribute to the inhibition of tumor growth by reactivation of antioxidative enzymes. This study advances our understanding of tumor growth inhibition by brewed GT in an animal model by demonstrating tissue localization of GTPs in correlation with inhibition of tumor growth. Our results suggest that the inhibition of tumor growth is due to GTP-mediated inhibition of oxidative stress and angiogenesis in the LAPC4 xenograft prostate tumor in SCID mice.
Henning, Susanne M.; Wang, Piwen; Said, Jonathan; Magyar, Clara; Castor, Brandon; Doan, Ngan; Tosity, Carmen; Moro, Aune; Gao, Kun; Li, Luyi; Heber, David
Polyphenols in brewed green tea inhibit prostate tumor xenograft growth by localizing to the tumor and decreasing oxidative stress and angiogenesis.
It has been demonstrated in various animal models that the oral administration of green tea (GT) extracts in drinking water can inhibit tumor growth, but the effects of brewed GT on factors promoting tumor growth, including oxidant damage of DNA and protein, angiogenesis and DNA methylation, have not been tested in an animal model. To explore these potential mechanisms, brewed GT was administered instead of drinking water to male severe combined immunodeficiency (SCID) mice with androgen-dependent human LAPC4 prostate cancer cell subcutaneous xenografts. Tumor volume was decreased significantly in mice consuming GT, and tumor size was significantly correlated with GT polyphenol (GTP) content in tumor tissue. There was a significant reduction in hypoxia-inducible factor 1-alpha and vascular endothelial growth factor protein expression. GT consumption significantly reduced oxidative DNA and protein damage in tumor tissue as determined by 8-hydroxydeoxyguanosine/deoxyguanosine ratio and protein carbonyl assay, respectively. Methylation is known to inhibit antioxidative enzymes such as glutathione S-transferase pi to permit reactive oxygen species promotion of tumor growth. GT inhibited tumor 5-cytosine DNA methyltransferase 1 mRNA and protein expression significantly, which may contribute to the inhibition of tumor growth by reactivation of antioxidative enzymes. This study advances our understanding of tumor growth inhibition by brewed GT in an animal model by demonstrating tissue localization of GTPs in correlation with inhibition of tumor growth. Our results suggest that the inhibition of tumor growth is due to GTP-mediated inhibition of oxidative stress and angiogenesis in the LAPC4 xenograft prostate tumor in SCID mice. PMID:22405694
Henning, Susanne M; Wang, Piwen; Said, Jonathan; Magyar, Clara; Castor, Brandon; Doan, Ngan; Tosity, Carmen; Moro, Aune; Gao, Kun; Li, Luyi; Heber, David
Enhanced expression of the ?4-galactosyltransferase 2 gene impairs mammalian tumor growth.
Altered N-glycosylation of membrane proteins is associated with malignant transformation of cells. We found that the expression of the ?4-galactosyltransferase 2 (?4GalT2) gene is decreased markedly during the transformation. Here, we examined whether the tumor growth activity of B16-F10 mouse melanoma cells can be reduced by the enhanced expression of the ?4GalT2 gene. We isolated a clone, B16-?4GalT2, showing its ?4GalT2 transcript 2.5 times higher than a control clone, B16-mock, by transducing its cDNA, and transplanted them subcutaneously into C57BL/6 mice to examine their tumor growth activity. The results showed that the average size of tumors formed with B16-mock cells is 13.1�0.76?mm, whereas that of tumors formed with B16-?4GalT2 cells is 5.1�1.13?mm (P<0.01) 2 weeks after transplantation. Immunohistochemical analyses showed that the apoptosis and the suppression of angiogenesis are induced in the tumors upon transduction of the ?4GalT2 gene. To pursue a clinical usefulness of the ?4GalT2 gene for suppressing human tumor growth, we injected adenoviruses carrying the human ?4GalT2 cDNA into HuH-7 human hepatocellular carcinomas developed in severe combined immunodeficient mice, and observed marked growth retardation of the tumors. The enhancement of the ?4GalT2 gene expression in tumors is one of the promising approaches to suppress human tumor growth. PMID:24903013
Tagawa, M; Shirane, K; Yu, L; Sato, T; Furukawa, S; Mizuguchi, H; Kuji, R; Kawamura, K; Takahashi, N; Kato, K; Hayakawa, S; Sawada, S; Furukawa, K
Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice
Membrane-bound proteases have recently emerged as critical mediators of tumorigenesis, angiogenesis, and metastasis. However, the mechanisms by which they regulate these processes remain unknown. As the cell surface serine protease fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts and pericytes in epithelial tumors, we set out to investigate the role of FAP in mouse models of epithelial-derived solid tumors. In this study, we demonstrate that genetic deletion and pharmacologic inhibition of FAP inhibited tumor growth in both an endogenous mouse model of lung cancer driven by the K-rasG12D mutant and a mouse model of colon cancer, in which CT26 mouse colon cancer cells were transplanted into immune competent syngeneic mice. Interestingly, growth of only the K-rasG12D�driven lung tumors was also attenuated by inhibition of the closely related protease dipeptidyl peptidase IV (DPPIV). Our results indicate that FAP depletion inhibits tumor cell proliferation indirectly, increases accumulation of collagen, decreases myofibroblast content, and decreases blood vessel density in tumors. These data provide proof of principle that targeting stromal cell�mediated modifications of the tumor microenvironment may be an effective approach to treating epithelial-derived solid tumors.
Santos, Angelica M.; Jung, Jason; Aziz, Nazneen; Kissil, Joseph L.; Pure, Ellen
Receptor tyrosine kinase inhibition suppresses growth of pediatric renal tumor cells in vitro
Purpose: Children who undergo standard therapy for renal tumors are at an increased risk for treatment sequelae such as congestive heart failure, abnormal trunk development, and secondary malignancies. Therefore, research on the use of novel chemotherapeutic agents with fewer side effects is justified. Recent experimental evidence suggests that growth factor receptors such as epidermal growth factor receptor (EGFR) and platelet-derived
Shalizeh Naraghi; Sami Khoshyomn; Joseph A DeMattia; Dennis W Vane
Growth promoting effect of recombinant interleukin I and tumor necrosis factor for human astrocytoma cells
Human IL I has been demonstrated to stimulate the growth of rat astrocytes in vitro. To determine if IL I has a similar growth promoting effect upon human brain cells, two astrocytoma cell lines were tested for their ability to incorporate ³H-thymidine in response to various types of IL I and tumor necrosis factor (TNF). The U373 astrocytoma was found
D. Giulian; C. A. Dinarello; D. C. Brown; L. B. Lachman
Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer.
As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis. PMID:24416386
Jardim-Perassi, Bruna Victorasso; Arbab, Ali S; Ferreira, L�via Carvalho; Borin, Thaiz Ferraz; Varma, Nadimpalli R S; Iskander, A S M; Shankar, Adarsh; Ali, Meser M; de Campos Zuccari, Debora Aparecida Pires
Genetic analysis of the growth curve of Rous sarcoma virus-induced tumors in chickens.
White Leghorn chicks homozygous for B19 MHC haplotype were selected for 18 generations on tumor regression after inoculation in the wing web with an SR-D strain of Rous sarcoma virus (RSV) at 4 wk of age. Each chick was assigned a tumor profile index (TPI) based on age at death and size of the tumor. During 18 generations, 2,010 birds were divergently selected on TPI for either progression or regression of the tumor (P and R lines). A Brody growth curve was fitted for each bird. Brody function parameters included the asymptotic tumor volume (A), the factor for increased growth in progression phase (K1), the factor for decreased growth in regression phase (K2), age at maximum volume (Tmax), and maximum volume of the tumor (Vmax). Tumor growth curves were found to be different according to line, sex, and restriction fragment pattern Y complex Rfp-Y MHC haplotype (Yw*15, Yw*16, and Yw*17). Within the P line, birds from the Yw*16 haplotype reached Vmax at an earlier age than Yw*15 and Yw*17, but with a lower Vmax value. Within the R line, tumor growth curves of birds from Yw*16 and Yw*17 haplotypes were similar. Rank correlations between the different parameters and TPI were low (between -0.26 and 0.36). Heritability estimated by the sire component was high for Vmax (0.73). Heritabilities of Tmax and K2 were moderate (0.20 to 0.23 for Tmax and 0.18 to 0.21 for K2) allowing these traits to be used as selection criteria. Heritabilities of A and K1 were lower than 0.12. Modeling the growth curve should contribute to better distinction between progressors and regressors. PMID:15384897
Praharaj, N; Beaumont, C; Dambrine, G; Soubieux, D; M�rat, L; Bouret, D; Luneau, G; Alletru, J-M; Pinard-Van der Laan, M-H; Thoraval, P; Mignon-Grasteau, S
Contributions of Cell Kill and Posttreatment Tumor Growth Rates to the Repopulation of Intracerebral 9L Tumors after Chemotherapy: An MRI Study
The drought of progress in clinical brain tumor therapy provides an impetus for developing new treatments as well as methods for testing therapeutics in animal models. The inability of traditional assays to simultaneously measure tumor size, location, growth kinetics, and cell kill achieved by a treatment complicates the interpretation of therapy experiments in animal models. To address these issues, tumor
Brian D. Ross; Yong-Jie Zhao; Eric R. Neal; Lauren D. Stegman; Matthew Ercolani; Oded Ben-Yoseph; Thomas L. Chenevert
Ephrin-A1 inhibits NSCLC tumor growth via induction of Cdx-2 a tumor suppressor gene
Background Tumor formation is a complex process which involves constitutive activation of oncogenes and suppression of tumor suppressor genes. Receptor EphA2 and its ligand ephrin-A1 form an important cell communication system with its functional role in cell-cell interaction and tumor growth. Loss of cell-cell adhesion is central to the cellular transformation and acquisition of metastatic potential. Claudins, the integrated tight junction (TJ) cell-cell adhesion proteins located on the apico-lateral portion of epithelial cells, functions in maintaining cell polarity. There is extensive evidence implicating Eph receptors and ephrins in malignancy, but the mechanisms how these molecular players affect TJ proteins and regulate tumor growth are not clear. In the present study we hypothesized that EphA2 signaling modulates claudin-2 gene expression via induction of cdx-2, a tumor suppressor gene in NSCLC cells. Methods The expression of EphA2, claudin-2 was determined in various NSCLC cell lines by using real-time quantitative polymerase chain reaction and Western blot analysis. The claudin-2 expression was also analyzed by immunofluorescence analysis. EphA2 and erk1/erk2 phosphorylation in ephrin-A1 activated cells was evaluated by Western blot analysis. The cell proliferation and tumor colony formation were determined by WST-1 and 3-D matrigel assays respectively. Results NSCLC cells over expressed receptor EphA2 and claudin-2. Ephrin-A1 treatment significantly down regulated the claudin-2 and EphA2 expression in NSCLC cells. The transient transfection of cells with vector containing ephrin-A1 construct (pcDNA-EFNA1) decreased the expression of claudin-2, EphA2 when compared to empty vector. In addition ephrin-A1 activation increased cdx-2 expression in A549 cells. In contrast over-expression of EphA2 with plasmid pcDNA-EphA2 up regulated claudin-2 mRNA expression and decreased cdx-2 expression. The transient transfection of cells with vector containing cdx-2 construct (pcMV-cdx-2) decreased the expression of claudin-2 in A549 cells. Moreover, silencing the expression of receptor EphA2 by siRNA significantly reduced claudin-2 expression and decreased cell proliferation and tumor formation. Furthermore, silencing cdx-2 gene expression before ephrin-A1 treatment increased claudin-2 expression along with increased cell proliferation and tumor growth in A549 cells. Conclusions Our study suggests that EphA2 signaling up-regulates the expression of the TJ-protein claudin-2 that plays an important role in promoting cell proliferation and tumor growth in NSCLC cells. We conclude that receptor EphA2 activation by ephrin-A1 induces tumor suppressor gene cdx-2 expression which attenuates cell proliferation, tumor growth and thus may be a promising therapeutic target against NSCLC.
Combined effects of X rays, Ro 03-8799, and hyperthermia on growth, necrosis, and cell proliferation in a mouse tumor
A mouse adenocarcinoma was treated with 20 Gy X rays, hyperthermia (30 minutes at 43 degrees C), Ro-03-8799, or a combination of two or three of these agents. Combined treatments increase growth delay in the tumor and this was greatest with the combination of all three modalities. Extensive amounts of necrosis were observed after the combined treatments. This effect was most pronounced after treatment modalities including hyperthermia. On the other hand, the radiation-induced micronucleus formation was more enhanced by the sensitizer than by hyperthermia. After X irradiation and combined treatments with X rays a G2-block was observed in DNA-histograms. Tetraploid cells appeared in large amounts that started DNA synthesis followed by necrosis. From these tumors it was impossible to obtain regular DNA-histograms. Tumor regression is a combined result of reduced cell renewal, increased cytogenetic damage, and development of necrosis.
George, K.C.; Streffer, C.; Pelzer, T.
The role of bone-marrow-derived cells in tumor growth, metastasis initiation and progression.
Emerging evidence from murine models suggests that tumor-specific endocrine factors systemically stimulate the quiescent bone marrow (BM) compartment, resulting in the expansion, mobilization and recruitment of BM progenitor cells. Discrete subsets of tumor-instigated BM-derived progenitor cells support tumor progression and metastasis by regulating angiogenesis, inflammation and immune suppression. Notably, clinical studies have begun to reveal that increased BM recruitment in tumors is associated with poor prognosis. Thus, the BM-derived tumor microenvironment is an attractive therapeutic target, and drugs targeting the components of the microenvironment are currently in clinical trials. Here, we focus on recent advances and emerging concepts regarding the intriguing role of BM-derived cells in tumor growth, metastasis initiation and progression, and we discuss future directions in the context of novel diagnostic and therapeutic opportunities. PMID:19665928
Gao, Dingcheng; Mittal, Vivek
Immunohistochemical evidence of association between ghrelin expression and tumor growth in esophageal carcinoma.
Background: Ghrelin, an orexigenic peptide, is primarily produced and secreted by the gastrointestinal tract. As far as we are aware of, there is no evidence of ghrelin expression in esophageal squamous cell carcinoma (ESCC). Materials and Methods: Two hundred and ten patients with ESCC who underwent surgical resection were enrolled in this study. We immunohistochemically investigated ghrelin expression in primary ESCC specimens and analyzed the relationship with clinicopathological factors. Results: High ghrelin expression was observed in 61 patients (29.0%). Depth of tumor invasion and histological differentiation were statistically associated with ghrelin expression. As for depth of tumor invasion, the deeper it was, the higher was the expression of ghrelin. Well-differentiated tumors had a significantly higher proportion of ghrelin-expressing cells than other types. Conclusion: Ghrelin expression correlated with tumor depth and tumor differentiation, suggesting an important role of ghrelin in tumor growth in ESCC. PMID:24922633
Omoto, Itaru; Matsumoto, Masataka; Uchikado, Yasuto; Kita, Yoshiaki; Sakurai, Toshihide; Sasaki, Ken; Setoyama, Tetsuro; Okumura, Hiroshi; Owaki, Tetsuhiro; Ishigami, Sumiya; Natsugoe, Shoji
A Novel Diterpene Suppresses CWR22Rv1 Tumor Growth In vivo through Antiproliferation and Proapoptosis
Androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers (PCa). As recurrent tumors restore AR activity independent of hormones, new therapies that abolish AR activity have been sought to prevent or delay the emergence of ablation-resistant disease. Here, we report that a novel abietane diterpene, 6-hydroxy-5,6- dehydrosugiol (HDHS), isolated from the stem bark of Cryptomeria
Feng-Min Lin; Chin-Hsien Tsai; Yu-Chih Yang; Wei-Chun Tu; Li-Ru Chen; Yun-Sa Liang; Sheng-Yang Wang; Lie-Fen Shyur; Shih-Chang Chien; Tai-Lung Cha; Pei-Wen Hsiao
Effects of photodynamic hyperthermal therapy with indocyanine green on tumor growth in a colon 26 tumor-bearing mouse model
The present study used indocyanine green (ICG) and a broadband light source apparatus [photodynamic hyperthermal therapy (PHT) group] in order to treat a colon 26 tumor-bearing mouse model. The other groups were administered either ICG alone (ICG group), light alone (light group) or no treatment (control group). Following the treatment, tumor growth was measured. Nine days after the treatment, the tumors were resected and histological and immunohistological examinations were performed. In the PHT group, the growth rates of the tumor tissues were significantly decreased compared with those observed in the other groups (P<0.05). The proportion of necrotic areas in the PHT and light groups were increased significantly compared with those observed in the ICG and control groups. However, there were no significant differences between the PHT and light groups. The proportion of Ki-67 in the PHT and light groups was less than that observed in the ICG and control groups. The number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells in the PHT group was significantly increased compared with that observed in the other groups. These data indicate that PHT is effective in vivo and in vitro.
PC Cell-Derived Growth Factor Mediates Tamoxifen Resistance and Promotes Tumor Growth of Human Breast Cancer Cells
PC cell-derived growth factor, also known as progranulin, is an Mr 88,000 growth factor (referred as PCDGF\\/GP88) overexpressed in human breast cancer. Antisense inhibition of PCDGF\\/GP88 expression in MDA- MB-468 cells inhibited tumor formation in nude mice. In estrogen recep- tor-positive cells, PCDGF\\/GP88 was expressed in response to estradiol and shown to mediate its mitogenic effect. Pathologic studies indicated that
Wisit Tangkeangsirisin; Jun Hayashi; Ginette Serrero
tRNAPhe and tRNAPro are the near-ultraviolet molecular targets triggering the growth delay effect.
The illumination of Escherichia coli cells with UVA light, 320 nm less than or equal to lambda less than or equal to 380 nm, triggers a transient growth and division delay. The built-in 4-thiouridine chromophore which absorbs light at 340 nm leads to the quantitative 8-13 crosslinking of a number of tRNA species corresponding to 50% of the bulk tRNA molecules. Determination of the tRNA acylation level by the various aminoacids shows that only the tRNA species acylated by Phe and Pro are strikingly affected in vivo. Both acylation levels decrease to less than 10% of their initial value during the illumination period, remain stable all along the growth lag and increase concomitantly with cell mass when growth resumes. Hence tRNA(Phe) and tRNA(Pro) are the UVA light molecular targets triggering growth delay and related effects of biological significance such as cell volume reduction, photoprotection and protection against UV mutagenesis (antiphotomutagenesis). PMID:2449211
Blondel, M O; Favre, A
Fibroblast-mediated acceleration of human epithelial tumor growth in vivo.
Transformed fibroblasts coinoculated with epithelial cells accelerated the growth and shortened the latency period of human epithelial tumors in athymic mice. Addition of NbF-1 fibroblasts caused epithelial tumors to grow from five marginally tumorigenic or "nontumorigenic" (nontumor-forming) human tumor cell lines or strains: PC-3 (prostate), WH (bladder), MDA-436 (breast), and cells derived from the ascites fluids of patients with metastatic renal pelvic or prostate cancers. Evidence for the human and epithelial nature of these experimental tumors was provided by histologic, immunohistochemical, Southern and dot-blot hybridization, and cytogenetic analyses. Transformed fibroblasts induced predominantly carcinosarcomas, whereas nontumorigenic fibroblasts (NIH 3T3) and lethally irradiated transformed fibroblasts induced exclusively carcinomas. The fibroblast-epithelial interaction appears to occur bidirectionally and does not result from cell fusion. Because coculture experiments in vitro did not demonstrate an increased cell proliferation, it appears that undefined host factors can influence tumor growth. This tumor model may be useful in drug-screening programs and in mechanistic studies of factors regulating human tumor growth and progression. Images
Camps, J L; Chang, S M; Hsu, T C; Freeman, M R; Hong, S J; Zhau, H E; von Eschenbach, A C; Chung, L W
Host endothelial S1PR1 regulation of vascular permeability modulates tumor growth.
Understanding vascular growth and maturation in developing tumors has important implications for tumor progression, spread, and ultimately host survival. Modulating the signaling of endothelial G protein-coupled receptors (GPCRs) in blood and lymphatic vessels can enhance or limit tumor progression. Sphingosine 1-phosphate receptor 1 (S1PR1) is a GPCR for circulating lysophospholipid S1P that is highly expressed in blood and lymphatic vessels. Using the S1PR1- enhanced green fluorescent protein (eGFP) mouse model in combination with intravital imaging and pharmacologic modulation of S1PR1 signaling, we show that boundary conditions of high and low S1PR1 signaling retard tumor progression by enhancing or destabilizing neovasculature integrity, respectively. In contrast, midrange S1PR1 signaling, achieved by receptor antagonist titration, promotes abundant growth of small, organized vessels and thereby enhances tumor progression. Furthermore, in vivo S1PR1 antagonism supports lung colonization by circulating tumor cells. Regulation of endothelial S1PR1 dynamically controls vascular integrity and maturation and thus modulates angiogenesis, tumor growth, and hematogenous metastasis. PMID:24740542
Sarkisyan, Gor; Gay, Laurie J; Nguyen, Nhan; Felding, Brunhilde H; Rosen, Hugh
Elevated epidermal growth factor receptor binding in plutonium-induced lung tumors from dogs
The objective of this study is to examine and characterize epidermal growth factor receptor (EGF-R) binding in inhaled plutonium-induced canine lung-tumor tissue and to compare it with that in normal canine lung tissue. Crude membrane preparations from normal and lung-tumor tissue from beagle dogs were examined in a radioreceptor assay, using {sup 125}I-labeled epidermal growth factor (EGF) as a ligand. Specific EGF receptor binding was determined in the presence of excess unlabeled EGF. We have examined EGF receptor binding in eight lung-tumor samples obtained from six dogs. Epidermal growth factor receptor binding was significantly greater in lung-tumor samples (31.38%) compared with that in normal lung tissue (3.76%). Scatchard plot analysis from the displacement assay revealed that there was no statistical difference in the binding affinity but significantly higher concentration of EGF-R sites in the lung-tumor tissue (619 fmol/mg) than in normal lung tissue (53 fmol/mg). The increase in EGF-R number in plutonium-induced dog lung tumors does not seem to correlate with increase in the initial lung burden exposure to plutonium. Our results demonstrate that there is a significant increase in EGF-R binding in inhaled plutonium-induced dog lung tumors.
Leung, F.C.; Bohn, L.R.; Dagle, G.E. (Pacific Northwest Lab., Richland, WA (USA))
Anti-IL-20 monoclonal antibody alleviates inflammation in oral cancer and suppresses tumor growth.
Interleukin-20 (IL-20) is a proinflammatory cytokine involved in rheumatoid arthritis, atherosclerosis, and osteoporosis. However, little is known about the role of IL-20 in oral cancer. We explored the function of IL-20 in the tumor progression of oral cancer. IL-20 expression levels in tumorous and nontumorous oral tissue specimens from 40 patients with four different stages oral cancer were analyzed with immunohistochemistry (IHC) staining and quantitative real-time PCR (qRT-PCR). Expression of IL-20 and its receptor subunits was higher in clinical oral tumor tissue than in nontumorous oral tissue. The role of IL-20 was examined in two oral cancer cell lines (OC-3 and OEC-M1). In vitro, IL-20 promoted TNF-?, IL-1?, MCP-1, CCR4, and CXCR4 and increased proliferation, migration, reactive oxygen species (ROS) production, and colony formation of oral cancer cells via activated STAT3 and AKT/JNK/ERK signals. To evaluate the therapeutic potential of anti-IL-20 monoclonal antibody 7E for treating oral cancer, an ex vivo tumor growth model was used. In vivo, 7E reduced tumor growth and inflammation in oral cancer cells. In conclusion, IL-20 promoted oral tumor growth, migration, and tumor-associated inflammation. Therefore, IL-20 may be a novel target for treating oral cancer, and anti-IL-20 monoclonal antibody 7E may be a feasible therapeutic. PMID:23002091
Hsu, Yu-Hsiang; Wei, Chi-Chen; Shieh, Dar-Bin; Chan, Chien-Hui; Chang, Ming-Shi
Modeling tumor growth in a complex evolving confinement using a diffuse domain approach
NASA Astrophysics Data System (ADS)
Understanding the spatiotemporal evolution of tumor growth represents an essential step towards engineering effective treatment for cancer patients. At the macroscopic scale, various biophysical models describing tumors as continuum fluids have been constructed, particularly on a Cartesian grid, where efficient numerical schemes are available to analyze the model for general tumor behaviors in a relatively unconfined space. For practical problems, however, tumors are often found in a confined sub-domain, which can even be dilated and distorted by the growing tumor within. To study such tumors, we adopt a novel diffuse domain approach that enables us to adapt a model to an evolving sub-domain and formulate the modified problem on a Cartesian grid to utilize existing numerical schemes. To demonstrate this approach, we adapt a diffuse-interface model presented in Wise et al. [2008, Three-dimensional multispecies nonlinear tumor growth - I Model and numerical method, J. Theor. Biol. 253, 524-543] to simulate lymphoma growth in a lymph node structure.
Chuang, Yao-Li; Lowengrub, John; Chen, Ying; Li, Xiangrong; Frieboes, Hermann; Cristini, Vittorio
Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy
The endothelial Tie1 receptor is ligand-less, but interacts with the Tie2 receptor for angiopoietins (Angpt). Angpt2 is expressed in tumor blood vessels, and its blockade inhibits tumor angiogenesis. Here we found that Tie1 deletion from the endothelium of adult mice inhibits tumor angiogenesis and growth by decreasing endothelial cell survival in tumor vessels, without affecting normal vasculature. Treatment with VEGF or VEGFR-2 blocking antibodies similarly reduced tumor angiogenesis and growth; however, no additive inhibition was obtained by targeting both Tie1 and VEGF/VEGFR-2. In contrast, treatment of Tie1-deficient mice with a soluble form of the extracellular domain of Tie2, which blocks Angpt activity, resulted in additive inhibition of tumor growth. Notably, Tie1 deletion decreased sprouting angiogenesis and increased Notch pathway activity in the postnatal retinal vasculature, while pharmacological Notch suppression in the absence of Tie1 promoted retinal hypervasularization. Moreover, substantial additive inhibition of the retinal vascular front migration was observed when Angpt2 blocking antibodies were administered to Tie1-deficient pups. Thus, Tie1 regulates tumor angiogenesis, postnatal sprouting angiogenesis, and endothelial cell survival, which are controlled by VEGF, Angpt, and Notch signals. Our results suggest that targeting Tie1 in combination with Angpt/Tie2 has the potential to improve antiangiogenic therapy.
D'Amico, Gabriela; Korhonen, Emilia A.; Anisimov, Andrey; Zarkada, Georgia; Holopainen, Tanja; Hagerling, Rene; Kiefer, Friedemann; Eklund, Lauri; Sormunen, Raija; Elamaa, Harri; Brekken, Rolf A.; Adams, Ralf H.; Koh, Gou Young; Saharinen, Pipsa; Alitalo, Kari
Dynamic tumor growth patterns in a novel murine model of colorectal cancer.
Colorectal cancer often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which polyps progress and which remain benign is difficult. We developed a novel long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived Apc(Min/+) mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of ?-catenin was higher in adenomas that became intratumoral carcinomas than those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features is needed to determine which features can be used to risk-stratify polyps for progression to colorectal cancer and potentially guide prevention strategies. PMID:24196829
Paul Olson, Terrah J; Hadac, Jamie N; Sievers, Chelsie K; Leystra, Alyssa A; Deming, Dustin A; Zahm, Christopher D; Albrecht, Dawn M; Nomura, Alice; Nettekoven, Laura A; Plesh, Lauren K; Clipson, Linda; Sullivan, Ruth; Newton, Michael A; Schelman, William R; Halberg, Richard B
Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies.
Compelling evidence for naturally occurring immunosurveillance against malignancies informs and justifies some current approaches toward cancer immunotherapy. However, some types of immune reactions have also been shown to facilitate tumor progression. For example, our previous studies showed that although experimental tumor growth is enhanced by low levels of circulating antibodies directed against the nonhuman sialic acid N-glycolyl-neuraminic acid (Neu5Gc), which accumulates in human tumors, growth could be inhibited by anti-Neu5Gc antibodies from a different source, in a different model. However, it remains generally unclear whether the immune responses that mediate cancer immunosurveillance vs. those responsible for inflammatory facilitation are qualitatively and/or quantitatively distinct. Here, we address this question using multiple murine tumor growth models in which polyclonal antibodies against tumor antigens, such as Neu5Gc, can alter tumor progression. We found that although growth was stimulated at low antibody doses, it was inhibited by high doses, over a linear and remarkably narrow range, defining an immune response curve (IRC; i.e., inverse hormesis). Moreover, modulation of immune responses against the tumor by altering antibody avidity or by enhancing innate immunity shifted the IRC in the appropriate direction. Thus, the dualistic role of immunosurveillance vs. inflammation in modulating tumor progression can be quantitatively distinguished in multiple model systems, and can occur over a remarkably narrow range. Similar findings were made in a human tumor xenograft model using a narrow range of doses of a monoclonal antibody currently in clinical use. These findings may have implications for the etiology, prevention, and treatment of cancer. PMID:24711415
Pearce, Oliver M T; L�ubli, Heinz; Verhagen, Andrea; Secrest, Patrick; Zhang, Jiquan; Varki, Nissi M; Crocker, Paul R; Bui, Jack D; Varki, Ajit
Tumors induce coordinate growth of artery, vein, and lymphatic vessel triads
Background Tumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they also can induce lymphatic vessel growth to facilitate fluid drainage and metastasis. These processes have generally been studied separately, so that it is not known how peritumoral blood and lymphatic vessels grow relative to each other. Methods The murine B16-F10 melanoma and chemically-induced squamous cell carcinoma models were employed to analyze large red-colored vessels growing between flank tumors and draining lymph nodes. Immunostaining and microscopy in combination with dye injection studies were used to characterize these vessels. Results Each peritumoral red-colored vessel was found to consist of a triad of collecting lymphatic vessel, vein, and artery, that were all enlarged. Peritumoral veins and arteries were both functional, as detected by intravenous dye injection. The enlarged lymphatic vessels were functional in most mice by subcutaneous dye injection assay, however tumor growth sometimes blocked lymph drainage to regional lymph nodes. Large red-colored vessels also grew between benign papillomas or invasive squamous cell carcinomas and regional lymph nodes in chemical carcinogen-treated mice. Immunostaining of the red-colored vessels again identified the clustered growth of enlarged collecting lymphatics, veins, and arteries in the vicinity of these spontaneously arising tumors. Conclusions Implanted and spontaneously arising tumors induce coordinate growth of blood and lymphatic vessel triads. Many of these vessel triads are enlarged over several cm distance between the tumor and regional lymph nodes. Lymphatic drainage was sometimes blocked in mice before lymph node metastasis was detected, suggesting that an unknown mechanism alters lymph drainage patterns before tumors reach draining lymph nodes.
Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs
The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti�VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.
Hedlund, Eva-Maria Eleonora; Yang, Xiaojuan; Zhang, Yin; Yang, Yunlong; Shibuya, Masabumi; Zhong, Weide; Sun, Baocun; Liu, Yizhi; Hosaka, Kayoko; Cao, Yihai
Nicotine Promotes Tumor Growth and Metastasis in Mouse Models of Lung Cancer
Background Nicotine is the major addictive component of tobacco smoke. Although nicotine is generally thought to have limited ability to initiate cancer, it can induce cell proliferation and angiogenesis in a variety of systems. These properties might enable nicotine to facilitate the growth of tumors already initiated. Here we show that nicotine significantly promotes the progression and metastasis of tumors in mouse models of lung cancer. This effect was observed when nicotine was administered through intraperitoneal injections, or through over-the-counter transdermal patches. Methods and Findings In the present study, Line1 mouse adenocarcinoma cells were implanted subcutaneously into syngenic BALB/c mice. Nicotine administration either by intraperitoneal (i.p.) injection or transdermal patches caused a remarkable increase in the size of implanted Line1 tumors. Once the tumors were surgically removed, nicotine treated mice had a markedly higher tumor recurrence (59.7%) as compared to the vehicle treated mice (19.5%). Nicotine also increased metastasis of dorsally implanted Line1 tumors to the lungs by 9 folds. These studies on transplanted tumors were extended to a mouse model where the tumors were induced by the tobacco carcinogen, NNK. Lung tumors were initiated in A/J mice by i.p. injection of NNK; administration of 1 mg/kg nicotine three times a week led to an increase in the size and the number of tumors formed in the lungs. In addition, nicotine significantly reduced the expression of epithelial markers, E-Cadherin and ?-Catenin as well as the tight junction protein ZO-1; these tumors also showed an increased expression of the ?7 nAChR subunit. We believe that exposure to nicotine either by tobacco smoke or nicotine supplements might facilitate increased tumor growth and metastasis. Conclusions Our earlier results indicated that nicotine could induce invasion and epithelial-mesenchymal transition (EMT) in cultured lung, breast and pancreatic cancer cells. This study demonstrates for the first time that administration of nicotine either by i.p. injection or through over-the-counter dermal patches can promote tumor growth and metastasis in immunocompetent mice. These results suggest that while nicotine has only limited capacity to initiate tumor formation, it can facilitate the progression and metastasis of tumors pre-initiated by tobacco carcinogens.
Davis, Rebecca; Rizwani, Wasia; Banerjee, Sarmistha; Kovacs, Michelle; Haura, Eric; Coppola, Domenico; Chellappan, Srikumar
CD200-expressing human basal cell carcinoma cells initiate tumor growth
Smoothened antagonists directly target the genetic basis of human basal cell carcinoma (BCC), the most common of all cancers. These drugs inhibit BCC growth, but they are not curative. Although BCC cells are monomorphic, immunofluorescence microscopy reveals a complex hierarchical pattern of growth with inward differentiation along hair follicle lineages. Most BCC cells express the transcription factor KLF4 and are committed to terminal differentiation. A small CD200+ CD45? BCC subpopulation that represents 1.63 � 1.11% of all BCC cells resides in small clusters at the tumor periphery. By using reproducible in vivo xenograft growth assays, we determined that tumor initiating cell frequencies approximate one per 1.5 million unsorted BCC cells. The CD200+ CD45? BCC subpopulation recreated BCC tumor growth in vivo with typical histological architecture and expression of sonic hedgehog-regulated genes. Reproducible in vivo BCC growth was achieved with as few as 10,000 CD200+ CD45? cells, representing ?1,500-fold enrichment. CD200? CD45? BCC cells were unable to form tumors. These findings establish a platform to study the effects of Smoothened antagonists on BCC tumor initiating cell and also suggest that currently available anti-CD200 therapy be considered, either as monotherapy or an adjunct to Smoothened antagonists, in the treatment of inoperable BCC.
Colmont, Chantal S.; BenKetah, Antisar; Reed, Simon H.; Hawk, Nga V.; Telford, William G.; Ohyama, Manabu; Udey, Mark C.; Yee, Carole L.; Vogel, Jonathan C.; Patel, Girish K.
News Note: Gene Therapy Method Slows Tumor Growth in Mice
NCI researchers have developed a novel method in mice of delivering genes to cancer cells, that when expressed, promote cell death. These genes, known as suicide genes, cause a cell to kill itself through a process known as apoptosis. The new technique uses the survivin gene promoter to express the suicide gene and induce apoptosis in cancer cells. This method of gene delivery effectively targeted tumor cells with a minimum effect on normal cells.
Carnosine retards tumor growth in vivo in an NIH3T3HER2\\/neu mouse model
BACKGROUND: It was previously demonstrated that the dipeptide carnosine inhibits growth of cultured cells isolated from patients with malignant glioma. In the present work we investigated whether carnosine also affects tumor growth in vivo and may therefore be considered for human cancer therapy. RESULTS: A mouse model was used to investigate whether tumor growth in vivo can be inhibited by
Christof Renner; Nadine Zemitzsch; Beate Fuchs; Kathrin D Geiger; Matthias Hermes; Jan Hengstler; Rolf Gebhardt; J�rgen Meixensberger; Frank Gaunitz
The Scatter Factor\\/Hepatocyte Growth Factor: c-Met Pathway in Human Embryonal Central Nervous System Tumor Malignancy
Embryonal central nervous system (CNS) tumors, which comprise medulloblastoma, are the most common malignant brain tumors in children. The role of the growth factor scat- ter factor\\/hepatocyte growth factor (SF\\/HGF) and its tyro- sine kinase receptor c-Met in these tumors has been until now completely unknown. In the present study, we show that human embryonal CNS tumor cell lines and
Yunqing Li; Bachchu Lal; Sherwin Kwon; Xing Fan; Usha Saldanha; Thomas E. Reznik; Eric B. Kuchner; Charles Eberhart; John Laterra; Roger Abounader
Loss of the innate immunity negative regulator IRAK-M leads to enhanced host immune defense against tumor growth
IRAK-M is a negative regulator of innate immunity signaling processes. Although attenuation of innate immunity may help to prevent excessive inflammation, it may also lead to compromised immune surveillance of tumor cells and contribute to tumor formation and growth. Here, we demonstrate that IRAK-M?\\/? mice are resistant to tumor growth upon inoculation with transplantable tumor cells. Immune cells from IRAK-M?\\/?
Qifa Xie; Lu Gan; Jianxia Wang; Ingred Wilson; Liwu Li
Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells.
Epidermal growth factor receptor (EGFR) targeting agents such as kinase inhibitors reduce tumor growth and progression. We have previously reported that EGFR is not only expressed by the tumor cells but by the tumor endothelial cells (EC) as well (Amin, D. N., Hida, K., Bielenberg, D. R., Klagsbrun, M., 2006. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res. 66, 2173-80). Thus, targeting tumor blood vessel EGFR may be a viable strategy for tumor growth inhibition. We describe here a melanoma xenograft model where the tumor cells express very little or no EGFR but the tumor blood vessels express activated EGFR. The EGFR kinase inhibitor, gefitinib (Iressa), retarded tumor growth with a size decrease of 38% compared to control mice, ostensibly due to targeting of the blood vessels. EC were isolated from tumors of gefitinib-treated mice. These EC were unable to proliferate in response to EGF and displayed relatively weaker activation of MAPK and AKT signaling in response to EGF compared to tumor EC isolated from vehicle-treated mice. In contrast, the tumor EC from gefitinib-treated mice expressed higher levels of VEGFR-2 both at the mRNA and protein level. In addition, these cells were less sensitive to EGFR kinase inhibitors in vitro but more sensitive to a VEGFR-2 kinase inhibitor. These results suggest that in tumor EC from gefitinib-treated mice there is a switch from dependence on EGFR activity to signaling via VEGFR-2. Our data provide a molecular rationale for combination therapies targeting both EGF and VEGF signaling on the tumor vasculature. PMID:18440031
Amin, Dhara N; Bielenberg, Diane R; Lifshits, Eugene; Heymach, John V; Klagsbrun, Michael
Personality-Targeted Interventions Delay the Growth of Adolescent Drinking and Binge Drinking
ERIC Educational Resources Information Center
Background: Personality factors are implicated in the vulnerability to adolescent alcohol misuse. This study examined whether providing personality-targeted interventions in early adolescence can delay drinking and binge drinking in high-risk youth. Methods: A randomised control trial was carried out with 368 adolescents recruited from years 9 and�
Conrod, Patricia J.; Castellanos, Natalie; Mackie, Clare
Both stromal cell and colonocyte epidermal growth factor receptors control HCT116 colon cancer cell growth in tumor xenografts
Colon cancer growth requires growth-promoting interactions between malignant colonocytes and stromal cells. Epidermal growth factor receptors (EGFR) are expressed on colonocytes and many stromal cells. Furthermore, EGFR is required for efficient tumorigenesis in experimental colon cancer models. To dissect the cell-specific role of EGFR, we manipulated receptor function on stromal cells and cancer cells. To assess the role of stromal EGFR, HCT116 human colon cancer cells were implanted into immunodeficient mice expressing dominant negative (DN) EgfrVelvet/+ or Egfr+/+. To assess the role of cancer cell EGFR, HCT116 transfectants expressing inducible DN-Egfr were implanted into immunodeficient mice. To dissect EGFR signals in vitro, we examined colon cancer cells in monoculture or in cocultures with fibroblasts for EGFR transactivation and prostaglandin synthase 2 (PTGS2) induction. EGFR signals were determined by blotting, immunostaining and real-time PCR. Tumor xenografts in EgfrVelvet/+ mice were significantly smaller than tumors in Egfr+/+ mice, with decreased proliferation (Ki67) and increased apoptosis (cleaved caspase-3) in cancer cells and decreased stromal blood vessels. Mouse stromal transforming growth factor alpha (TGFA), amphiregulin (AREG), PTGS2 and Il1b and interleukin-1 receptor 1 (Il1r1) transcripts and cancer cell beta catenin (CTNNB1) and cyclin D1 (CCND1) were significantly lower in tumors obtained from EgfrVelvet/+ mice. DN-EGFR HCT116 transfectants also formed significantly smaller tumors with reduced mouse Areg, Ptgs2, Il1b and Il1r1 transcripts. Coculture increased Caco-2 phospho-active ERBB (pERBB2), whereas DN-EGFR in Caco-2 cells suppressed fibroblast PTGS2 and prostaglandin E2 (PGE2). In monoculture, interleukin 1 beta (IL1B) transactivated EGFR in HCT116 cells. Stromal cell and colonocyte EGFRs are required for robust EGFR signals and efficient tumor growth, which involve EGFR�interleukin-1 crosstalk.
Bissonnette, Marc
Cytotoxic activity and absence of tumor growth stimulation of standardized mistletoe extracts in human tumor models in vitro.
Mistletoe extracts are widely used in complementary and alternative cancer therapy in Europe. The extracts possess cytotoxic, as well as immunostimulatory effects. However, some investigators have suggested that low doses of mistletoe extracts could also induce tumor growth. The mistletoe extracts Helixor A, Helixor M and Helixor P were investigated for growth inhibitory and stimulatory effects in a panel of 38 human tumor cell lines in vitro. Mistletoe lectin I (ML-1), adriamycin and interleukin-6 (IL-6) were used as reference compounds. All three mistletoe preparations showed cytotoxic activity [T/C (Test/Control) < 30%]: Helixor P was the most potent, followed by Helixor M and Helixor A with IC50 (50% inhibitory concentration) values of 68.4, 114 and 133 microg/ml, respectively. The IC50 values of ML-1 and adriamycin were 0.026 and 0.069 microg/ml. None of the human tumor cell lines in the panel showed growth stimulation (T/C (Test/Control) > 125%) by the mistletoe extracts or ML-1, apart from two exceptions in the colon carcinoma cell line HCC-2998, in which Helixor M and ML-1 showed a marginal stimulation (TIC 128% and 131%, respectively) at one concentration only. Further investigations into the latter effect of Helixor M and ML-1 in the HCC-2998 line using five different proliferation assays, modified cell culture conditions and the identical production charge of mistletoe extract, as well as a new one, did not confirm the previous observation. It was concluded that the marginal stimulation found in the earlier experiments was a statistical coincidence. Helixor mistletoe preparations and ML-1 have cytotoxic activity and do not stimulate tumor cell proliferation in vitro which is in accordance with previous scientifically based observations on aqueous mistletoe extracts. PMID:17352237
Kelter, Gerhard; Schierholz, J�rg M; Fischer, Imma U; Fiebig, Heinz-Herbert
The impact of CD4 +CD25 + Treg on tumor specific CD8 + T cell cytotoxicity and cancer
There is sufficient evidence to suggest that tumor growth elicits specific immune responses, including CD8+ and CD4+ T cell responses that may delay tumor growth and could potentially be harnessed to eradicate cancer. Nevertheless the frequent outcome of cancer is lethality associated with uncontrolled growth and dissemination of tumor cells. The failure of the immune response may be naturally programmed
Khashayarsha Khazaie; Harald von Boehmer
Modulation of CXCL-8 expression in human melanoma cells regulates tumor growth, angiogenesis, invasion, and metastasis
CXCL-8, a chemokine secreted by melanoma and stromal cells, serves as a growth and angiogenic factor for melanoma progression. This study evaluated how modulation of CXCL-8 levels in melanoma cell lines with different tumorigenic and metastatic potentials affected multiple tumor phenotypes. A375P cells (CXCL-8 low expressor) were stably transfected with a CXCL-8 mammalian expression vector to overexpress CXCL-8, whereas A375SM cells (CXCL-8 high expressor) were transfected with a CXCL-8 antisense expression vector to suppress CXCL-8 expression. Subsequent cell proliferation, migration, invasion, and soft-agar colony formation were analyzed, and in vivo tumor growth and metastasis were evaluated using mouse xenograft models. Our data demonstrate that overexpression of CXCL-8 significantly enhanced primary tumor growth and lung metastasis, accompanied by increased microvessel density in vivo, as compared with vector control-transfected cells. We also observed increased clonogenic ability, growth, and invasive potential of CXCL-8 overexpressing cells in vitro. Knockdown of CXCL-8 using an antisense vector resulted in increased cell death and reduced tumor growth relative to control. Taken together, these data confirm that CXCL-8 expression plays a critical role in regulating multiple cellular phenotypes associated with melanoma growth and metastasis.
Wu, Sheng; Singh, Seema; Varney, Michelle L; Kindle, Scott; Singh, Rakesh K
Modulation of CXCL-8 expression in human melanoma cells regulates tumor growth, angiogenesis, invasion, and metastasis.
CXCL-8, a chemokine secreted by melanoma and stromal cells, serves as a growth and angiogenic factor for melanoma progression. This study evaluated how modulation of CXCL-8 levels in melanoma cell lines with different tumorigenic and metastatic potentials affected multiple tumor phenotypes. A375P cells (CXCL-8 low expressor) were stably transfected with a CXCL-8 mammalian expression vector to overexpress CXCL-8, whereas A375SM cells (CXCL-8 high expressor) were transfected with a CXCL-8 antisense expression vector to suppress CXCL-8 expression. Subsequent cell proliferation, migration, invasion, and soft-agar colony formation were analyzed, and in vivo tumor growth and metastasis were evaluated using mouse xenograft models. Our data demonstrate that overexpression of CXCL-8 significantly enhanced primary tumor growth and lung metastasis, accompanied by increased microvessel density in vivo, as compared with vector control-transfected cells. We also observed increased clonogenic ability, growth, and invasive potential of CXCL-8 overexpressing cells in vitro. Knockdown of CXCL-8 using an antisense vector resulted in increased cell death and reduced tumor growth relative to control. Taken together, these data confirm that CXCL-8 expression plays a critical role in regulating multiple cellular phenotypes associated with melanoma growth and metastasis. PMID:23342280
Wu, Sheng; Singh, Seema; Varney, Michelle L; Kindle, Scott; Singh, Rakesh K
A recombinant decoy comprising EGFR and ErbB-4 inhibits tumor growth and metastasis
EGF-like growth factors control tumor progression, as well as evasion from the toxic effects of chemotherapy. Accordingly, antibodies targeting the cognate receptors, such as EGFR/ErbB-1 and the co-receptor HER2/ErbB-2, are widely used to treat cancer patients, but agents that target the EGF-like growth factors are not available. To circumvent the existence of 11 distinct ErbB ligands, we constructed a soluble fusion protein (hereinafter: TRAP-Fc) comprising truncated extracellular domains of EGFR/ErbB-1 and ErbB-4. The recombinant TRAP-Fc retained high affinity ligand binding to EGF-like growth factors and partially inhibited growth of a variety of cultured tumor cells. Consistently, TRAP-Fc displayed an inhibitory effect in xenograft models of human cancer, as well as synergy with chemotherapy. Additionally, TRAP-Fc inhibited invasive growth of mammary tumor cells and reduced their metastatic seeding in the lungs of animals. Taken together, the activities displayed by TRAP-Fc reinforce critical roles of EGF-like growth factors in tumor progression, and they warrant further tests of TRAP-Fc in pre-clinical models.
Lindzen, Moshit; Carvalho, Silvia; Starr, Alex; Ben-Chetrit, Nir; Pradeep, Chaluvally-Raghavan; Kostler, Wolfgang J.; Rabinkov, Aaron; Lavi, Sara; Bacus, Sarah S.; Yarden, Yosef
UVB-irradiated apoptotic cells induce accelerated growth of co-implanted viable tumor cells in immune competent mice.
The presence of a solid tumor is the result of a complex balance between rejection, tolerance and regeneration in which the interactions of tumor cells with cells of the host immune system contribute strongly to the final outcome. Here we report on a model where lethally UVB-irradiated cells cause accelerated growth of viable tumor cells in vitro and in allogeneic immune competent mice. UVB-irradiated tumor cells alone did not form tumors and failed to induce tolerance for a second challenge with the same allogeneic tumor. Our data show an important role for dying cells in promoting accelerated tumor cell growth of a small number of viable tumor cells in a large inoculum of UVB-irradiated tumor cells. This occurs when viable and dying/dead tumor cells are in close proximity, suggesting that mobile factors contribute to growth promotion. The anti-inflammatory and growth promoting properties of apoptotic cells are based on several independent effects. UVB-irradiated apoptotic cells directly release a growth promoting activity and clearance by macrophages of apoptotic cells is accompanied by the secretion of IL10, TGF�, and PGE2. Growth promotion is even observed with dying heterologous cells implying a conserved mechanism. Future experiments should focus on the effects of dying tumor cells generated in vivo on the outgrowth of surviving tumor cells which is prone to have implications for cancer therapy. PMID:23194071
Chaurio, Ricardo; Janko, Christina; Schorn, Christine; Mauer�der, Christian; Bilyy, Rostyslav; Gaipl, Udo; Schett, Georg; Berens, Christian; Frey, Benjamin; Munoz, Luis E
Bioluminescent imaging (BLI) to improve and refine traditional murine models of tumor growth and metastasis
Bioluminescent imaging (BLI) permits sensitive in vivo detection and quantification of cells specifically engineered to emit visible light. Three stable human tumor cell lines\\u000a engineered to express luciferase were assessed for their tumorigenicity in subcutaneous, intravenous and spontaneous metastasis\\u000a models. Bioluminescent PC-3M-luc-C6 human prostate cancer cells were implanted subcutaneously into SCID-beige mice and were\\u000a monitored for tumor growth and response
Darlene E. Jenkins; Yoko Oei; Yvette S. Hornig; Shang-Fan Yu; Joan Dusich; Tony Purchio; Pamela R. Contag
Integrating kinetic models for Simulating tumor growth in Monte Carlo Simulation of ECT systems
We have developed an integrated framework for linking tumor growth models directly into a Monte Carlo simulation algorithm for positron emission tomography and single-photon emission computed tomography systems. Tumors are approximated either by analytically defined five-dimensional (x,y,z,tgeometry,tactivity) compartments or by compound cellular lattice inserts. Both representation models can be placed into arbitrarily complex tomographic or mathematical phantoms. Various models for
Joerg Peter; Wolfhard Semmler
Coexpression of hypoxia-inducible factor 1-alpha and vascular endothelial growth factor in Wilms' tumor
Background\\/Purpose: Hypoxia-inducible factor 1 alpha (HIF-1?) is an important transcriptional factor responsible for regulating expression of the angiogenic cytokine, vascular endothelial growth factor (VEGF). Little information is available regarding factors involved in the hypoxic cascade, such as HIF or VEGF in Wilms' tumor. We concomitantly evaluate the expression of HIF-1? and VEGF in ex vivo human Wilms' tumor specimens. Methods:
John Karth; Fernando A. Ferrer; Elizabeth Perlman; Collen Hanrahan; Jonathan W. Simons; John P. Gearhart; Ronald Rodriguez
Compositions and methods for homoconjugates of antibodies which induce growth arrest or apoptosis of tumor cells
US Patent & Trademark Office Database
This invention discloses monoclonal antibodies (MAbs) which have little or no signaling activity as monomers become potent anti-tumor agents when they are converted into homoconjugates. The homoconjugates exert anti-growth activity by signaling G.sub.0 /G.sub.1 arrest or apoptosis, depending upon which cell surface molecule they bind. This activity is specific and does not require an Fc portion. These conjugates are potent, anti-tumor agents.
Inhibition of the growth of some hormone dependent tumors by d Trp 6 LHRH
We have investigated the effects of chronic administration of D-Trp6-LH-RH on the growth of various hormone dependent tumors in rats and mice. Treatment of male Copenhagen F-1 rats bearing the\\u000a Dunning R-3327 H prostate adenocarcinoma with 25 ?g of D-Trp6-LH-RH bid for 21 days significantly reduced tumor weight and volume as compared to controls. Serum LH, prolactin and testosterone\\u000a levels
Andrew V. Schally; Tommie W. Redding; Ana Maria Comaru-Schally
Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.
Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3? activation, while p38? phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors. PMID:24789042
Ruma, I Made Winarsa; Putranto, Endy Widya; Kondo, Eisaku; Watanabe, Risayo; Saito, Ken; Inoue, Yusuke; Yamamoto, Ken-Ichi; Nakata, Susumu; Kaihata, Masaji; Murata, Hitoshi; Sakaguchi, Masakiyo
Hypoxia-regulated over expression of soluble VEGFR2 controls angiogenesis and inhibits tumor growth
Vascular endothelial growth factors (VEGFs) are found at high levels in hypoxic tumors. As major components directing pathologic neo-vascularisation, they regulate stromal reactions. Consequently, novel strategies, targeting and inhibiting VEGF over-production upon hypoxia offer considerable potential for modern anti-cancer therapies controlling rather than destroying tumor angiogenesis. Here we report the design of a vector expressing the soluble form of VEGF receptor-2 (sVEGFR2) driven by a hypoxia responsive element (HRE)-regulated promoter. To enable in vivo imaging by infrared visualization, mCherry and IFP1.4 coding sequences were built into the vector. Plasmid construction was validated through transfection into embryonic human kidney HEK293 and murine B16F10 melanoma cells. sVEGFR2 was expressed in hypoxic conditions only, confirming that the gene was regulated by the HRE-promoter. sVEGFR2 was found to bind efficiently and specifically to murine and human VEGF-A, reducing the growth of tumor and endothelial cells as well as impacting angiogenesis in vitro. The hypoxia-conditioned sVEGFR2 expression was shown to be functional in vivo: tumor angiogenesis was inhibited and, on stable transfection of B16F10 melanoma cells, tumor growth was reduced. Enhanced expression of sVEGFR2 was accompanied by a modulation in levels of VEGF-A. The resulting balance reflected the effect on tumor growth and on the control of angiogenesis. A concomitant increase of intra-tumor oxygen tension also suggested an influence on vessel normalization. The possibility to express an angiogenesis regulator as sVEGFR2, in a hypoxia-conditioned manner, significantly opens new strategies for tumor vessel-controlled normalization and the novel design of adjuvants for combined cancer therapies.
Collet, Guillaume; Lamerant-Fayel, Nathalie; Tertil, Magdalena; El Hafny-Rahbi, Bouchra; Stepniewski, Jacek; Guichard, Alan; Foucault-Collet, Alexandra; Klimkiewicz, Krzysztof; Petoud, Stephane; Matejuk, Agata; Grillon, Catherine; Jozkowicz, Alicja; Dulak, Jozef; Kieda, Claudine
Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth.
Fibroblasts are the most abundant "non-cancerous" cells in tumors. However, it remains largely unknown how these cancer-associated fibroblasts (CAFs) promote tumor growth and metastasis, driving chemotherapy resistance and poor clinical outcome. This review summarizes new findings on CAF signaling pathways and their emerging metabolic phenotypes that promote tumor growth. Although it is well established that altered cancer metabolism enhances tumor growth, little is known about the role of fibroblast metabolism in tumor growth. New studies reveal that metabolic coupling occurs between catabolic fibroblasts and anabolic cancer cells, in many types of human tumors, including breast, prostate, and head & neck cancers, as well as lymphomas. These catabolic phenotypes observed in CAFs are secondary to a ROS-induced metabolic stress response. Mechanistically, this occurs via HIF1-alpha and NF?B signaling, driving oxidative stress, autophagy, glycolysis and senescence in stromal fibroblasts. These catabolic CAFs then create a nutrient-rich microenvironment, to metabolically support tumor growth, via the local stromal generation of mitochondrial fuels (lactate, ketone bodies, fatty acids, glutamine, and other amino acids). New biomarkers of this catabolic CAF phenotype (such as caveolin-1 (Cav-1) and MCT4), which are reversible upon treatment with anti-oxidants, are strong predictors of poor clinical outcome in various types of human cancers. How cancer cells metabolically reprogram fibroblasts can also help us to understand the effects of cancer cells at an organismal level, explaining para-neoplastic phenomena, such as cancer cachexia. In conclusion, cancer should be viewed more as a systemic disease, that engages the host-organism in various forms of energy-transfer and metabolic co-operation, across a whole-body "ecosystem". PMID:24486645
Martinez-Outschoorn, Ubaldo E; Lisanti, Michael P; Sotgia, Federica
Paracrine and autocrine growth mechanisms in tumor metastasis to specific sites with particular emphasis on brain and lung metastasis
Once metastatic cells successfully seed at distant sites, their clinical detection and danger to the host are dependent on growth to form gross metastases. Metastatic tumor cells proliferate in response to local paracrine growth factors and inhibitors, and their growth also depends on production and responses to autocrine growth factors. A major organ-derived (paracrine) growth factor from lung tissue-conditioned medium
Garth L. Nicolson
Growth-inhibitory Activity and Downregulation of the Class II Tumor-suppressor Gene H-rev107 in Tumor Cell Lines and Experimental Tumors
The H-rev107 gene is a new class II tumor suppressor, as defined by its reversible downregulation and growth-inhibiting capacity in HRAS transformed cell lines. Overexpression of the H-rev107 cDNA in HRAS-transformed ANR4 hepatoma cells or in FE-8 fibroblasts resulted in 75% reduction of colony formation. Cell populations of H-rev107 transfectants showed an attenuated tumor formation in nude mice. Cells explanted from tumors or maintained in cell culture for an extended period of time no longer exhibited detectable levels of the H-rev107 protein, suggesting strong selection against H-rev107 expression in vitro and in vivo. Expression of the truncated form of H-rev107 lacking the COOH-terminal membrane associated domain of 25 amino acids, had a weaker inhibitory effect on proliferation in vitro and was unable to attenuate tumor growth in nude mice. The H-rev107 mRNA is expressed in most adult rat tissues, and immunohistochemical analysis showed expression of the protein in differentiated epithelial cells of stomach, of colon and small intestine, in kidney, bladder, esophagus, and in tracheal and bronchial epithelium. H-rev107 gene transcription is downregulated in rat cell lines derived from liver, kidney, and pancreatic tumors and also in experimental mammary tumors expressing a RAS transgene. In colon carcinoma cell lines only minute amounts of protein were detectable. Thus, downregulation of H-rev107 expression may occur at the level of mRNA or protein.
Sers, Christine; Emmenegger, Urban; Husmann, Knut; Bucher, Katharina; Andres, Ann-Catherine; Schafer, Reinhold
Portal venous tumor growth-type of hepatocellular carcinoma without liver parenchyma tumor nodules: a case report.
The patient was a 43-year-old man with chronic hepatitis B without history of hepatocellular carcinoma (HCC), who was first diagnosed with thrombosis in right portal vein trunk and portal vein branches and ruptured esophageal varices in October 2011. He underwent endoscopic variceal ligation, but ruptured repeatedly. Despite anti-coagulant therapy, the thrombosis expanded from right portal vein trunk to upper mesenteric vein in March 2012. Computed tomography (CT) scan showed that portal vein thrombosis had low density from early to late phase. No focal liver lesions were identified by CT scan or ultrasound, and alpha-fetoprotein (AFP) was within normal range. He died by intractable esophageal variceal bleeding in April 2012. Pathological examination of autopsy specimen showed that portal vein thrombosis was consistent with poorly-differentiated HCC. The portal vein tumor thrombosis (PVTT) had only a few tumor vessels, which were compressed by fibromatous change originating from HCC formation, so were represented as low-density lesions from arterial to portal phase of CT. In addition, PVTT was negative for AFP, so representing serum value of AFP within normal range. PVTT had positive staining for c-kit, which is a liver stem cell marker. Liver tumors in the whole liver parenchyma were not found pathologically. PVTT might have the characteristics of presumed liver cancer stem cells. We experienced the first case of HCC only in portal vein without liver parenchyma tumor nodules, with difficult differential diagnosis from a non-malignant portal vein thrombosis. We also reported new tumor profiles of the portal venous tumor growth- type of HCC. PMID:24114829
Saito, Masaya; Seo, Yasushi; Yano, Yoshihiko; Uehara, Keiichiro; Hara, Shigeo; Momose, Kenji; Hirano, Hirotaka; Yokozaki, Hiroshi; Yoshida, Masaru; Azuma, Takeshi
Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms
Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1?, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPAR? pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1? axis as a potential therapeutic target for this presently incurable disease.
Herroon, Mackenzie K.; Rajagurubandara, Erandi; Hardaway, Aimalie L.; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela
Activated Abl kinase inhibits oncogenic transforming growth factor-? signaling and tumorigenesis in mammary tumors
Transforming growth factor-? (TGF-?) is a ubiquitous cytokine with dual roles in tumor suppression and promotion, and these dichotomous functions have frustrated the development of therapies targeting oncogenic signaling by TGF-?. In comparison, Abl is well established as an initiator of hematopoietic cancers; however, a clear role for Abl in regulating solid tumor development remains elusive. Here, we investigated the role of Abl in TGF-?-mediated epithelial-mesenchymal transition (EMT) in normal and metastatic mammary epithelial cells (MECs). In doing so, we identified Abl as an essential regulator of MEC morphology and showed that Abl inactivation was sufficient to induce phenotypic and transcriptional EMT in normal MECs. Increasing Abl activity in metastatic MECs resulted in their complete morphological reversion, restored their cytostatic response to TGF-?, and blocked their secretion of matrix metalloproteinases induced by TGF-?. Constitutively active Abl expression blocked TGF-?-responsive mammary tumor growth in mice, while Imatinib therapy afforded no clinical benefit in mice bearing mammary tumors. Collectively, this investigation establishes Abl as a potent mediator of MEC identity, and as a suppressor of oncogenic TGF-? signaling during mammary tumorigenesis. Notably, our findings strongly caution against the use of pharmacological Abl antagonists in the treatment of developing and progressing mammary tumors.�Allington, T. M., Galliher-Beckley, A. J., Schiemann, W. P. Activated Abl kinase inhibits oncogenic transforming growth factor-? signaling and tumorigenesis in mammary tumors.
Allington, Tressa M.; Galliher-Beckley, Amy J.; Schiemann, William P.
Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide
Caveolin-1 (Cav-1) is a critical regulator of tumor progression in a variety of cancers where it has been shown to act as either a tumor suppressor or tumor promoter. In glioblastoma multiforme, it has been previously demonstrated to function as a putative tumor suppressor. Our studies here, using the human glioblastoma-derived cell line U-87MG, further support the role of Cav-1 as a negative regulator of tumor growth. Using a lentiviral transduction approach, we were able to stably overexpress Cav-1 in U-87MG cells. Gene expression microarray analyses demonstrated significant enrichment in gene signatures corresponding to downregulation of MAPK, PI3K/AKT and mTOR signaling, as well as activation of apoptotic pathways in Cav-1-overexpressing U-87MG cells. These same gene signatures were later confirmed at the protein level in vitro. To explore the ability of Cav-1 to regulate tumor growth in vivo, we further show that Cav-1-overexpressing U-87MG cells display reduced tumorigenicity in an ectopic xenograft mouse model, with marked hypoactivation of MAPK and PI3K/mTOR pathways. Finally, we demonstrate that Cav-1 overexpression confers sensitivity to the most commonly used chemotherapy for glioblastoma, temozolomide. In conclusion, Cav-1 negatively regulates key cell growth and survival pathways and may be an effective biomarker for predicting response to chemotherapy in glioblastoma.
Quann, Kevin; Gonzales, Donna M.; Mercier, Isabelle; Wang, Chenguang; Sotgia, Federica; Pestell, Richard G.; Lisanti, Michael P.; Jasmin, Jean-Francois
Vascular CD39/ENTPD1 directly promotes tumor cell growth by scavenging extracellular adenosine triphosphate.
Extracellular adenosine triphosphate (ATP) is known to boost immune responses in the tumor microenvironment but might also contribute directly to cancer cell death. CD39/ENTPD1 is the dominant ectonucleotidase expressed by endothelial cells and regulatory T cells and catalyzes the sequential hydrolysis of ATP to AMP that is further degraded to adenosine by CD73/ecto-5'-nucleotidase. We have previously shown that deletion of Cd39 results in decreased growth of transplanted tumors in mice, as a result of both defective angiogenesis and heightened innate immune responses (secondary to loss of adenosinergic immune suppression). Whether alterations in local extracellular ATP and adenosine levels as a result of CD39 bioactivity directly affect tumor growth and cytotoxicity has not been investigated to date. We show here that extracellular ATP exerts antitumor activity by directly inhibiting cell proliferation and promoting cancer cell death. ATP-induced antiproliferative effects and cell death are, in large part, mediated through P2X(7) receptor signaling. Tumors in Cd39 null mice exhibit increased necrosis in association with P2X(7) expression. We further demonstrate that exogenous soluble NTPDase, or CD39 expression by cocultured liver sinusoidal endothelial cells, stimulates tumor cell proliferation and limits cell death triggered by extracellular ATP. Collectively, our findings indicate that local expression of CD39 directly promotes tumor cell growth by scavenging extracellular ATP. Pharmacological or targeted inhibition of CD39 enzymatic activity may find utility as an adjunct therapy in cancer management. PMID:21390184
Feng, Lili; Sun, Xiaofeng; Csizmadia, Eva; Han, Lihui; Bian, Shu; Murakami, Takashi; Wang, Xin; Robson, Simon C; Wu, Yan
Model of avascular tumor growth and response to low dose exposure
NASA Astrophysics Data System (ADS)
A single level cellular automata model is described and used to simulate early tumor growth, and the response of the tumor cells under low dose radiation affects. In this model the cell cycle of the population of normal and cancer cells is followed. The invasion mechanism of the tumor is simulated by a local factor that takes into account the microenvironment hardness to cell development, in a picture similar to the AMTIH model. The response of normal and cancer cells to direct effects of radiation is tested for various models and a model of bystander response is implemented.
Rodriguez Aguirre, J. M.; Custidiano, E. R.
Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model.
Dyslipidemia has been associated with an increased risk for developing cancer. However, the implicated mechanisms are largely unknown. To explore the role of dyslipidemia in breast cancer growth and metastasis, we used the apolipoprotein E (ApoE) knockout mice (ApoE(-/-)), which exhibit marked dyslipidemia, with elevated circulating cholesterol and triglyceride levels in the setting of normal glucose homeostasis and insulin sensitivity. Non-metastatic Met-1 and metastatic Mvt-1 mammary cancer cells derived from MMTV-PyVmT/FVB-N transgenic mice and c-Myc/vegf tumor explants respectively, were injected into the mammary fat pad of ApoE(-/-) and wild-type (WT) females consuming a high-fat/high-cholesterol diet and tumor growth was evaluated. ApoE(-/-) mice exhibited increased tumor growth and displayed a greater number of spontaneous metastases to the lungs. Furthermore, intravenous injection of Mvt-1 cells resulted in a greater number of pulmonary metastases in the lungs of ApoE(-/-) mice compared with WT controls. To unravel the molecular mechanism involved in enhanced tumor growth in ApoE(-/-) mice, we studied the response of Mvt-1 cells to cholesterol in vitro. We found that cholesterol increased Akt(S473) phosphorylation in Mvt-1 cells as well as cellular proliferation, whereas cholesterol depletion in the cell membrane abrogated Akt(S473) phosphorylation induced by exogenously added cholesterol. Furthermore, in vivo administration of BKM120, a small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), alleviated dyslipidemia-induced tumor growth and metastasis in Mvt-1 model with a concomitant decrease in PI3K/Akt signaling. Collectively, we suggest that the hypercholesterolemic milieu in the ApoE(-/-) mice is a favorable setting for mammary tumor growth and metastasis. PMID:22469977
Alikhani, N; Ferguson, R D; Novosyadlyy, R; Gallagher, E J; Scheinman, E J; Yakar, S; LeRoith, D
A Novel Monoclonal Antibody to Secreted Frizzled Related Protein 2 Inhibits Tumor Growth
Secreted frizzled related protein 2 (SFRP2) is overexpressed in human angiosarcoma and breast cancer, and stimulates angiogenesis via activation of the calcineurin/ NFATc3 pathway. There are conflicting reports in the literature as to whether SFRP2 is an antagonist or agonist of �-catenin. The aims of these studies were to assess the effects of SFRP2 antagonism on tumor growth and Wnt-signaling, and to evaluate whether SFRP2 is a viable therapeutic target. The anti-angiogenic and anti-tumor properties of SFRP2 monoclonal antibody (mAb) were assessed using in vitro proliferation, migration, and tube formation assays; and in vivo angiosarcoma and triple negative breast cancer models. Wnt-signaling was assessed in endothelial and tumor cells treated with SFRP2 mAb using Western blotting. Pharmacokinetic (PK) and biodistribution data were generated in tumor-bearing and non-tumor bearing mice. SFRP2 mAb was shown to induce anti-tumor and anti-angiogenic effects in vitro, and inhibit activation of �-catenin and NFATc3 in endothelial and tumor cells. Treatment of SVR angiosarcoma allografts in nude mice with the SFRP2 mAb decreased tumor volume by 58% compared to control (p=0.004). Treatment of MDA-MB-231 breast carcinoma xenografts with SFRP2 mAb decreased tumor volume by 52% (p=0.03) compared to control, while bevacizumab did not significantly reduce tumor volume. Pharmacokinetic studies show the antibody is long circulating in the blood and preferentially accumulates in SFRP2-positive tumors. In conclusion, antagonizing SFRP2 inhibits activation of �-catenin and NFATc3 in endothelial and tumor cells, and is a novel therapeutic approach to inhibiting angiosarcoma and triple negative breast cancer.
Fontenot, Emily; Rossi, Emma; Mumper, Russell; Snyder, Stephanie; Siamakpour-Reihani, Sharareh; Ma, Ping; Hilliard, Eleanor; Bone, Bradley; Ketelsen, David; Santos, Charlene; Patterson, Cam; Klauber-DeMore, Nancy
Controlling brain tumor growth via intraventricular administration of an AAV vector encoding IFN-?
Glioblastoma multiforme (GBM) is the most aggressive type of all primary brain tumors, with an overall median survival < 1 year after diagnosis. Despite introduction of multimodal treatment approaches, the prognosis has not improved significantly over the last 50 years. In this study we investigated the effect of intracerebroventricular injection of an AAV vector encoding human interferon-beta (hIFN-?) on glioblastoma growth. Recently, we found that peri-tumoral parenchymal transduction with an AAV vector encoding hIFN-? was exceptionally efficient in eradicating GBM brain tumors. However the extensive infiltration and migration displayed by glioblastoma cells in patients may leave a significant number of tumor cells outside a local therapeutic zone created by intraparenchymal delivery of AAV vectors. Here we show that pretreatment of mice via intracerebroventricular (ICV) infusion of an AAV vector encoding hIFN-? (AAV-IFN-?) completely prevents tumor growth in an orthotopic model of GBM. Furthermore, ICV infusion of AAV-IFN-? into mice bearing pre-established U87 intracranial tumors improved their survival compared to mice infused via the same route with a control AAV vector. These data suggest that ICV injection of AAV vectors encoding anti-tumor proteins is a promising approach deserving further consideration for the treatment of GBM.
Meijer, Dimphna H.; Maguire, Casey A.; LeRoy, Stanley G.; Sena-Esteves, Miguel
Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature.
We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20-26 �C; however, these subthermoneutral temperatures cause mild chronic cold stress, activating thermogenesis to maintain normal body temperature. When stress is alleviated by housing at thermoneutral ambient temperature (30-31 �C), we observe a striking reduction in tumor formation, growth rate and metastasis. This improved control of tumor growth is dependent upon the adaptive immune system. We observe significantly increased numbers of antigen-specific CD8(+) T lymphocytes and CD8(+) T cells with an activated phenotype in the tumor microenvironment at thermoneutrality. At the same time there is a significant reduction in numbers of immunosuppressive MDSCs and regulatory T lymphocytes. Notably, in temperature preference studies, tumor-bearing mice select a higher ambient temperature than non-tumor-bearing mice, suggesting that tumor-bearing mice experience a greater degree of cold-stress. Overall, our data raise the hypothesis that suppression of antitumor immunity is an outcome of cold stress-induced thermogenesis. Therefore, the common approach of studying immunity against tumors in mice housed only at standard room temperature may be limiting our understanding of the full potential of the antitumor immune response. PMID:24248371
Kokolus, Kathleen M; Capitano, Maegan L; Lee, Chen-Ting; Eng, Jason W-L; Waight, Jeremy D; Hylander, Bonnie L; Sexton, Sandra; Hong, Chi-Chen; Gordon, Christopher J; Abrams, Scott I; Repasky, Elizabeth A
Inhibition of endogenous reverse transcriptase antagonizes human tumor growth
Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon\\/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to
Ilaria Sciamanna; Matteo Landriscina; Carmine Pittoggi; Michela Quirino; Cristina Mearelli; Rosanna Beraldi; Elisabetta Mattei; Annalucia Serafino; Alessandra Cassano; Paola Sinibaldi-Vallebona; Enrico Garaci; Carlo Barone; Corrado Spadafora
Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice.
Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). Previously, we reported on the development of an anti-AM antibody that potently inhibits tumor cell proliferation in vitro and tumor growth in vivo. Here, we report the effect of anti-AM receptor antibodies (alphaAMRs) on angiogenesis and tumor growth. We demonstrate that alphaAMRs decrease in a dose-dependent manner the growth of U87 glioblastoma cells and HT-29 colorectal cancer cells, but not A549 lung cancer cells, in vitro. In vivo, AM in Matrigel plugs induces angiogenesis by promoting recruitment of endothelial cells, pericytes, myeloid precursor cells, and macrophages and by promoting channel formation. Remarkably, systemic administration of alphaAMRs every 3 d markedly reduced neovascularization of Matrigel plugs in a dose-dependent fashion, as demonstrated by reduced numbers of the recruited cells and vessel structures. Several human tumor xenografts in athymic mice were used to examine the effect of alphaAMR treatment on tumor angiogenesis and growth. AlphaAMR treatment significantly suppressed the growth of glioblastoma, lung, and colon tumors. Histological examination of alphaAMR-treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial and pericyte cells, and increased tumor cell apoptosis. These findings support the conclusion that alphaAMR treatment inhibits tumor growth by suppression of angiogenesis and tumor growth and suggest that AMRs may be useful therapeutic targets. PMID:19546305
Kaafarani, Itidal; Fernandez-Sauze, Samantha; Berenguer, Caroline; Chinot, Olivier; Delfino, Christine; Dussert, Christophe; Metellus, Philippe; Boudouresque, Fran�oise; Mabrouk, Kamel; Grisoli, Fran�ois; Figarella-Branger, Dominique; Martin, Pierre-Marie; Ouafik, L'Houcine
Oncolytic HSV and erlotinib inhibit tumor growth and angiogenesis in a novel malignant peripheral nerve sheath tumor xenograft model.
Malignant peripheral nerve sheath tumors (MPNSTs), driven in part by hyperactive Ras and epidermal growth factor receptor (EGFR) signaling, are often incurable. Testing of therapeutics for MPNST has been hampered by lack of adequate xenograft models. We previously documented that human MPNST cells are permissive for lytic infection by oncolytic herpes simplex viruses (oHSV). Herein we developed and characterized a xenograft model of human MPNST and evaluated the antitumor effects of oHSV mutants (G207 and hrR3) and the EGFR inhibitor, erlotinib. Additive cytotoxicity of these agents was found in human MPNST cell lines, suggesting that EGFR signaling is not critical for virus replication. Mice bearing human MPNST tumors treated with G207 or hrR3 by intraperitoneal or intratumoral injection showed tumor-selective virus biodistribution, virus replication, and reduced tumor burden. oHSV injection demonstrated more dramatic antitumor activity than erlotinib. Combination therapies showed a trend toward an increased antiproliferative effect. Both oHSV and erlotinib were antiangiogenic as measured by proangiogenic gene expression, effect on endothelial cells and xenograft vessel density. Overall, oHSVs showed highly potent antitumor effects against MPNST xenografts, an effect not diminished by EGFR inhibition. Our data suggest that inclusion of MPNSTs in clinical trials of oHSV is warranted. PMID:17235305
Mahller, Yonatan Y; Vaikunth, Sachin S; Currier, Mark A; Miller, Shyra J; Ripberger, Maria C; Hsu, Ya-Hsuan; Mehrian-Shai, Ruty; Collins, Margaret H; Crombleholme, Timothy M; Ratner, Nancy; Cripe, Timothy P
Intrauterine growth restriction transiently delays alveolar formation and disrupts retinoic acid receptor expression in the lung of female rat pups
Background We showed that intrauterine growth restriction (IUGR) increases distal airspace wall thickness at birth (postnatal age 0; P0) in rat pups (saccular stage of lung development). However, that report did not assess whether the saccular phenotype persisted postnatally or occurred in males or females. Nor did that report identify a potential molecular pathway for the saccular phenotype at P0. We hypothesized that IUGR persistently delays alveolar formation and disrupts retinoic acid receptor (RAR) mRNA and protein levels in the lung of rat pups in postnatal age- and sex-specific manners. Methods IUGR was induced in pregnant rats by bilateral uterine artery ligation. Alveolar formation and expression of RAR?, ?, and ? were quantified at P0, P6 (alveolar stage), and P21 (postalveolarization). Results IUGR increased distal airspace wall thickness in female pups at P0 only. IUGR did not affect male pups at any age. IUGR transiently increased lung RAR? protein abundance, which inhibits alveolar formation, at P0 in female pups. Serum retinol concentration was normal at all ages. Conclusions IUGR alone is not sufficient to persistently delay postnatal alveolar formation or disrupt expression RARs. We speculate that for IUGR to delay alveolar formation postnatally, a second insult is necessary.
Yang, Yan; Fitzhugh, Melanie; Metcalfe, Drew; Oman, Jake; Hale, Merica; Dong, Li; Wang, Zheng-Ming; Yu, Xing; Callaway, Christopher W.; O'Brien, Elizabeth; McKnight, Robert A.; Lane, Robert H.; Albertine, Kurt H.
Glioma Tumor Stem-Like Cells Promote Tumor Angiogenesis and Vasculogenesis via Vascular Endothelial Growth Factor and Stromal-Derived Factor 1
Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow�derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow�derived EPC in a vascular endothelial growth factor�dependent and stromal-derived factor 1�dependent manner.
Folkins, Chris; Shaked, Yuval; Man, Shan; Tang, Terence; Lee, Christina R.; Zhu, Zhenping; Hoffman, Robert M.; Kerbel, Robert S.
Massive T-Lymphocyte Infiltration into the Host Stroma Is Essential for Fibroblast Growth Factor-2-Promoted Growth and Metastasis of Mammary Tumors via Neovascular Stability
Inflammation in the tumor stroma greatly influences tumor development. In the present study, we investigated the roles of fibroblast growth factor (FGF)-2-induced chronic inflammation in the development of 4T1 murine mammary tumors. Administration of FGF-2 into the tumor inoculation site during the initial phase of tumor growth enhanced tumor growth and pulmonary metastasis as well as microvessel density in tumor tissues in normal but not in nude mice. Infiltration of T lymphocytes and macrophages, recruitment of pericytes/vascular mural cells in neovascular walls, and the expression levels of cyclooxygenase (COX)-2 and vascular endothelial growth factor A (VEGFA) were also enhanced in the FGF-2-activated host stroma of normal mice. In addition, FGF-2-induced tumor growth and metastasis was abrogated by administration of either an immunosuppressant, FK506, or a COX-2 inhibitor. FGF-2 enhanced prostaglandin E2 secretion in cultured T lymphocytes. In addition, VEGFA secretion was increased in a co-culture of T lymphocytes and fibroblasts in vitro. These results indicate that the massive infiltration of T lymphocytes into FGF-2-activated host stroma during the initial phase of tumor growth enhances neovascular stability by regulating endogenous COX-2 and VEGFA levels because both compounds are known to play important roles in marked 4T1 mammary <