A new study published in the journal Nature Cell Biology discribes how researchers havediscovered how normal cells in tumors can enhance and 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 (OSUCCC ? James), the study examines what happens when normal cells called fibroblasts in mouse mammary tumors lose an important tumor-suppressor gene called phosphatase and tensin homolog deleted on chromosome 10 or PTEN (pronounced ?P-TEN?).
The tumour suppressor PTEN is a PI (phosphoinositide) 3-phosphatase that can inhibit cellular proliferation, survival and growth by inactivating PI 3-kinase-dependent signalling. It also suppresses cellular motility through mechanisms that may be partially independent of phosphatase activity. PTEN is one of the most commonly lost tumour suppressors in human cancer, and its deregulation is also implicated in several other diseases.
New strategies for controlling tumor growth
The findings suggest new strategies for controlling tumor growth by developing drugs that disrupt the communication between tumor cells and the normal cells within the tumor. They also provide insight into the mechanisms that control the co-evolution of cancer cells and surrounding normal cells in tumors, and they demonstrate how the Pten gene normally suppresses cancer development, the researchers say.
Reprogramming gene activity
?Our study is the first to define a specific pathway in tumor fibroblasts that reprograms gene activity and the behavior of multiple cell types in the tumor microenvironment, including tumor cells themselves,? says co-principal investigator Michael Ostrowski, MD, professor and chair of molecular and cellular biochemistry.
?Along with increasing basic knowledge about how tumors grow and spread, these findings have direct translational implications for the treatment of breast-cancer patients,? says Ostrowski, who is a member of the OSUCCC ? James Molecular Biology and Cancer Genetics program.
The researchers found that Pten regulates a molecule called microRNA-320 (miR-320), and that the loss of PTEN leads to a dramatic drop in levels of that molecule in a tumor fibroblast. With little miR-320 around, levels of a protein called ETS2 (pronounced Ets-two) rise in the fibroblast.
Finally, the abundance of ETS2 activates a number of genes that cause the fibroblast to secrete more than 50 factors that stimulate the proliferation and invasiveness of nearby cancer cells. It also causes the reprogramming of other fibroblasts in the tumor and throughout the mammary gland.
Non-cancer cells in the tumor microenvironment
?The cancer field has long focused solely on targeting tumor cells for therapy,? says co-principal investigator Gustavo Leone, associate professor of molecular virology, immunology and medical genetics. ?Our work suggests that modulation of a few key molecules such as miR-320 int non-cancer cells in the tumor microenvironment might be sufficient to impede the most malignant properties of tumor cells.?
Ostrowski, Leone and their colleagues began this study by examining human invasive breast tumors from 126 patients for microRNA changes after PTEN loss. Using mouse models, they found that miR-320 levels and ETS2 levels were inversely correlated in human breast-tumor tissue, suggesting that PTEN and miR-320 work together to block ETS2 function and suppress tumor growth. They also noted that miR-320 in mammary fibroblasts influences the behavior of multiple cell types, making it a critical molecule for suppressing epithelial tumors.
Inhibiting tumor-promoting factors
miR-320 functions as a regulatory switch in normal fibroblasts that operates to inhibit the secretion of more than 50 tumor-promoting factors (i.e., a tumor-promoting secretome). In doing so, it blocks the expression of genes in other cell types in the tumor microenvironment and suppresses tumor-cell growth and invasiveness.
Overall, loss of PTEN in tumor fibroblasts results in downregulation of miR-320 and release of the secretome factors. This causes the genetic reprogramming of neighboring endothelial and epithelial cells of the mammary gland, inciting profound changes in these cells that are typical of malignant tumors.
?Remarkably, the molecular signature of the miR-320 secretome could distinguish normal breast tissue from tumor tissue, and it predicted the outcome in breast-cancer patients,? says Leone, who is also a member of the Ohio State University Comprehensive Cancer Center ? James Molecular Biology and Cancer Genetics program. ?This underscores the potential clinical importance of the PTEN-miR-320 regulatory pathway on human breast cancer.?
Funding from the National Cancer Institute, National Institute of Child Health and Human Development, the Komen Breast Cancer Foundation and Evelyn Simmers Charitable Trust supported this research.
For more information:
 Bronisz A, Godlewski J, Wallace JA, Merchant AS, Nowicki MO, Mathsyaraja H, et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat Cell Biol. 2011 Dec 18. doi: 10.1038/ncb2396. [Epub ahead of print].
 Leslie NR, Downes CP. PTEN function: how normal cells control it and tumour cells lose it.
Biochem J. 2004 Aug 15;382(Pt 1):1-11.
Utafiti wa hivi karibuni uliochapishwa katika jarida la Nature Cell Biology unaelezea jinsi watafiti walivyogundua jinsi seli za kawaida katika uvimbe zinaweza kuongeza na kuongeza ukuaji wa uvimbe. Utafiti huo ulifanywa na watafiti wa Chuo Kikuu cha Ohio, na unafanywa na Chuo Kikuu cha Chuo Kikuu cha Ohio, na Chuo Kikuu cha Ohio, na Chuo Kikuu cha Chuo Kikuu cha Ohio, na Chuo Kikuu cha Ohio. Hospitali ya Saratani ya Arthur G. James na Taasisi ya Utafiti ya Richard J. Solove (OSUCCC? "Kama ilivyoelezwa hapo juu, ""kila chembe ya kawaida inayoitwa fibroblasts katika uvimbe wa mama ya panya hupoteza jeni muhimu la kuzuia uvimbe linaloitwa phosphatase na homoloji ya tensin iliyofutwa kwenye kromosomu ya 10 au PTEN.""" PTE ni phospho-inositide 3-phosphatase ambayo inaweza kuzuia kuenea kwa seli, kuishi na ukuaji kwa kuzuia ishara ya kinase ya 3-kinase. Pia huzuia mwendo wa seli kupitia utaratibu ambao unaweza kuwa huru kwa sehemu ya shughuli ya phosphatase. PTEN ni moja ya suppressors tumors kawaida waliopotea katika kansa ya binadamu, na deregulation yake pia ni kuhusishwa katika magonjwa mengine kadhaa. Utafiti huo unaonyesha mbinu mpya za kudhibiti ukuaji wa uvimbe kwa kuendeleza dawa ambazo huvuruga mawasiliano kati ya seli za uvimbe na seli za kawaida ndani ya uvimbe. "Wanafanya utafiti wa kugundua jinsi chembe za saratani na chembe za kawaida zinazozunguka tumbo zinavyoweza ""kuendelea"" pamoja na kuondoa saratani, na jinsi chembe za P-TEN zinavyoweza ""kuzuia"" maendeleo ya saratani." "Utafiti wetu ni wa kwanza kufafanua njia maalum katika fibroblasts ya uvimbe ambayo hupanga upya shughuli za jeni na tabia ya aina nyingi za seli katika mazingira madogo ya uvimbe, pamoja na seli za uvimbe wenyewe. """ "Mwanasayansi Michael Ostrowski, MD, profesa wa ""Biokemia ya Molekuli na Seli"" anasema: ""Hii ni kweli." Pamoja na kuongeza maarifa ya msingi juu ya jinsi uvimbe unavyoongezeka na kuenea, matokeo haya yana athari za moja kwa moja za tafsiri kwa matibabu ya wagonjwa wa saratani ya matiti. Ostrovsky, ambaye ni mwanachama wa OSUCCC? James Programu ya Biolojia ya Molekuli na Genetics ya Saratani. Watafiti walipata kwamba PTE inasimamia molekuli inayoitwa microRNA-320 (miR-320) na kwamba kupoteza PTE kunasababisha kupungua kwa viwango vya molekuli hiyo katika fibroblast ya uvimbe. Kwa sababu ya miR-320 ndogo, viwango vya protini inayoitwa ETS2 (inajulikana kama Ets-two) huongezeka katika fibroblast. Hatimaye, ETS2 nyingi huamsha jeni kadhaa ambazo husababisha fibroblast kutenganisha zaidi ya sababu 50 ambazo huchochea kuenea na uvamizi wa seli za saratani zilizo karibu. Pia husababisha programu mpya ya fibroblasts nyingine katika uvimbe na katika tezi ya maziwa. Seli zisizo za saratani katika mazingira ya uvimbe: Utafiti wa saratani umekuwa ukielekezwa kwa muda mrefu kwa kuelekeza seli za uvimbe kwa matibabu. "Gustavo Leone, profesa wa molekuli virolojia, immunolojia na genetics ya matibabu, alisema: ""Hii ni moja ya mambo muhimu katika utafiti wa virusi." "Utafiti wetu unaonyesha kwamba modulation ya molekuli chache muhimu kama vile miR320 katika seli zisizo za kansa katika mazingira ya kiini ya uvimbe inaweza kuwa ya kutosha kuzuia mali mbaya zaidi ya seli za uvimbe. """ Ostrowski, Leone na wenzake walianza utafiti huu kwa kuchunguza uvimbe wa kifua wa binadamu kutoka kwa wagonjwa 126 kwa mabadiliko ya microRNA baada ya kupoteza PTEN. Kwa kutumia mifano ya panya, walipata kuwa viwango vya miR320 na viwango vya ETS2 vilihusiana kwa njia ya kinyume katika tishu ya uvimbe wa kifua cha binadamu, ikidokeza kwamba PTEN na miR320 hufanya kazi pamoja kuzuia kazi ya ETS2 na kuzuia ukuaji wa uvimbe. MiR-320 katika fibroblasts ya maziwa huathiri tabia ya aina nyingi za seli, na kuifanya kuwa molekuli muhimu kwa kuzuia uvimbe wa epithelial. MiR320 ni kifaa cha kudhibiti katika fibroblasts ya kawaida ambayo inafanya kazi kuzuia sekreti ya zaidi ya 50 ya sababu za kukuza uvimbe (yaani, secretome ya kukuza uvimbe). Kwa kufanya hivyo, inazuia usemi wa jeni katika aina nyingine za chembe katika mazingira madogo ya uvimbe na kuzuia ukuaji wa chembe za uvimbe na uvamizi. Kwa ujumla, kupoteza PTEN katika fibroblasts ya uvimbe husababisha kudhibiti chini ya miR320 na kutolewa kwa sababu za secretome. Hii husababisha programu mpya ya maumbile ya seli za endothelial na epithelial za kibofu cha maziwa, na kusababisha mabadiliko makubwa katika seli hizi ambazo ni za kawaida kwa uvimbe mbaya. "Kama ilivyoelezwa hapo juu, ""saini ya molekuli ya miR-320 secretome inaweza kutofautisha tishu ya kawaida ya kifua kutoka tishu ya uvimbe, na ilitabiri matokeo katika wagonjwa wa saratani ya kifua.""" "Leo, ambaye pia ni mwanachama wa Chuo Kikuu cha Jimbo la Ohio Comprehensive Cancer Center, anasema: ""Ninaamini kwamba kuna uwezekano mkubwa wa kuambukizwa virusi vya saratani." James Programu ya Biolojia ya Molekuli na Genetics ya Saratani. "Hii inaonyesha umuhimu wa kliniki wa njia ya udhibiti wa PTEN-MR320 kwenye kansa ya matiti ya binadamu.""" Utafiti huo ulifadhiliwa na Taasisi ya Kitaifa ya Saratani, Taasisi ya Kitaifa ya Afya ya Watoto na Maendeleo ya Binadamu, Shirika la Komen la Saratani ya Matiti na Evelyn Simmers Charitable Trust. Kwa maelezo zaidi, angalia: B.A.Godlewski, J.W.Wallace, J.A.Merchant, M.O. Nowitzki, M.H.Mathsyaraya, et al. Utaratibu wa kuunda mfumo wa tumbo kwa kutumia miR-320 Nat Cell Biol. (Mwanzo 18:10-13) Kwa nini? [Epub kabla ya kuchapishwa]. Leslie, Downes CP Utaratibu wa PTEN: jinsi chembe za kawaida zinavyoidhibiti na chembe za uvimbe hupoteza. Biochem J. 2004 Aug 15;382 (Pt 1):1-11.