pancreatic cancer remains difficult to treat , despite the recent advances in various anti - cancer therapies . because of difficulties in early diagnosis , most patients with pancreatic cancer receive chemotherapy and/or surgical treatment.1 therefore , prevention and early diagnosis are important for reducing incidence of pancreatic cancer . in recent japanese cohort study , there was an inverse relationship between the risk of pancreatic cancer and 3-polyunsaturated fatty acids ( pufas ) consumption.2 macek et al.3 studied plasma fatty acid composition in patients with pancreatic cancer . they found that longer - term survival of pancreatic cancer patients was connected with higher consumption of eicosapentaenoic acid ( epa ) and docosahexaenoic acid ( dha ) . the proportions of epa and dha in plasma phospholipid displayed negative trend with tumor staging.3 he et al.4 conducted a prospective cohort study for associations of fish types and fish preparation methods with pancreatic cancer risk in washington state . mohammed et al.5 determined the impact of w3-pufas on pancreatic intraepithelial neoplasms ( panins ) and their progression to pancreatic ductal adenocarcinoma ( pdac ) using 3-fatty acid desaturase ( fat-1 ) transgenic mice , which can convert 6-pufa to 3-ftty acids endogenously . they found a dramatic reduction in incidence of pdac in compound fat-1-p48(cre/+)-lsl - kras(g12d/+ ) mice compared to p48(cre/+)-lsl - kras(g12d/+ ) mice . in addition , significant reductions of pancreatic ducts with carcinoma and panin 3 lesions were observed in the compound transgenic mice . the levels of 3-pufas were much higher in pancreas of compound transgenic mice than in those of p48(cre/+)-lsl - kras(g12d/+ ) mice . fat-1-p48(cre/+)-lsl - kras(g12d/+ ) mice showed lower levels of proliferating cell nuclear antigen , cox-2 , 5-lipoxygenase ( 5-lox ) , 5-lox - activating protein , bcl-2 , and cyclin d1 than p48(cre/+)-lsl - kras(g12d/+ ) mice.5 these studies suggest that dietary 3-pufas may prevent development of pancreatic cancer in high - risk individuals . in addition , dha undergoes rapid uptake into cells which is sustained for the length of the treatment course . therefore , this regimen is appropriate for therapies for cancer patients.6 even though dha is a promising therapeutic agent for pancreatic cancer , there has been relatively little studies to explain how dha supplementation inhibits the development of pancreatic cancer . pancreatic carcinogenesis involves the resistance to apoptosis,7,8 hyper - proliferation with abnormal wnt/-catenin signaling,9,10 invasion,11 and expression of pro - angiogenic growth factors.12 dha , one of 3-pufas , exhibits good anti - inflammatory and anti - neoplastic properties by inducing oxidative stress,13 inhibiting -catenin accumulation,14 and suppressing degradation of extracellular cellular matrix proteins15 and expression of growth factors16,17 in pancreatic cancer cells . here , we review the anti - cancer mechanisms of dha in pancreatic carcinogenesis based on the recent studies . pancreatic cancer cells show resistance to apoptosis in several levels of apoptotic pathways.18,19 pancreatic cancer cells have been reported to produce non - functional death signal receptors,20 overexpress bcl - family proteins,7 or block caspase activation.8 these kinds of apoptosis evasion make the cancer cells become tolerant to cancer therapies , and promote cancer progression.8 recent study showed that the primary pancreatic cancers expressed toll - like receptor ( tlr ) 2 , 4 , and 9 . tlr - specific stimulation resulted in the activation of mitogen - activated protein kinase signaling and expression of vegf and platelet - derived growth factor ( pdgf ) . moreover , tlr activation prompted the expression of bcl - xl to induce tumor cell proliferation in pancreatic cancer.21 tgf- has a dual role in tumorigenesis , acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages.22 witte et al.22 reported that proteinase - activated receptor 2 ( par2 ) is a novel regulator of tgf- signaling in pancreatic cancer . since par2 controls the expression of tgf- type i receptor , anaplastic lymphoma kinase ( alk)5 , par2 may also impact signaling by other tgf- superfamily members that signal through alk5 . thus , par2 could represent a molecular linker between pancreatic cancer development and cancer - related cachexia . dysregulation of wnt/-catenin signaling is found in many types of cancers , including pancreatic cancer.9,10 during embryotic development and tissue homeostasis , wnt/-catenin signaling regulates fundamental processes , such as proliferation , polarity , and fate determination of cells.23 when wnt signal is absent , the scaffolding protein axin recruits glycogen synthase kinase-3 ( gsk3 ) , casein kinse 1 ( ck1 ) , adenomatous polyposis coli gene product , and -catenin , forming a destruction complex . ck1 and gsk3 are kinase proteins which phosphorylate serine 45 and threonine 41 , serine 33 , and serine 37 of -catenin , respectively.23 this phosphorylated -catenin serves as a binding site for the e3 ubiquitin ligase , -transducin repeat - containing protein . however , when wnt binds to frizzled receptors , the axin complex loses its destruction activity , leading to accumulation of -catenin in cytoplasm . high concentration of -catenin in cytoplasm eventually causes its nuclear translocation.24 in nucleus , -catenin acts as a transcription cofactor for genes related to cell proliferation , migration , and matrix metallo - proteases secretion.10 constitutively active wnt/-catenin signaling is a feature of pancreatic cancer.9 one of the reasons why survival rate of pancreatic cancer is so low is due to a high risk of local invasion and metastasis in pancreatic cancer . the incidence of lymphatic metastasis in pancreatic cancer is about 65.3% to 89.0%.11 metastasization begins with invasion of tumor cells into surrounding tissue . tumor cells release hydrolytic enzymes such as matrix metallo - proteases and disintegrate extracellular matrix ( ecm ) , then migrate to blood or lymphatic vessels.25 rapidly growing cancer cells need more blood vessels in order to meet their metabolic requirements . vegf has been reported to increase vascular permeability , stimulate endothelial cell proliferation and migration , and promote endothelial cell survival.26 in addition , vegf and its receptor are up - regulated in pancreatic cancer cells.12 in 1998 , hawkins et al.27 reported that apoptotic death of human mia - paca-2 pancreatic cancer cells induced by pufas varies with double bond number and involves an oxidative mechanism . they found correlations between the number of fatty acid double bonds and the proportion of apoptotic cells . the extent of pufas - induced lipid peroxidation , measured as malondialdehyde , also correlated with the proportion of apoptosis . this is the first study showing the relation of oxidative stress and apoptosis in pancreatic cancer cells . later , merendino et al.28 reported that dha exhibited active glutathione ( gsh ) extrusion and increased reactive oxygen species ( ros ) which mediate apoptotic cell death of human paca-44 pancreatic cancer cells.7 inhibition of gsh efflux completely reversed apoptosis of pancreatic cancer cells.7 fukui et al.29 also showed that epa and dha induced ros accumulation and caspase-8-dependent cell death in human pancreatic cancer cells . they also demonstrated that 5% fish oil supplementation reduced the growth of mia - paca-2 xenografts in athymic nude mice.29 we recently summarized that oxidized dha leads to dna adduct formation . oxidative dna damage triggers cell cycle arrest and apoptosis by p53-dependent and p53-independent pathways in cancer cells.30 zhang et al.31 reported that dha and epa inhibits proliferation and induce apoptosis of human sw 1990 pancreatic cancer cells by down - regulating cyclin e expression . dha suppressed pancreatic cancer cell growth by inhibiting activation of wnt/-catenin signaling.14 dha inhibited the accumulation of -catenin in cytoplasm and nucleus , and decreased overall -catenin protein level in human pancreatic cancer cells , sw1990 and panc-1.14 dha increased the binding of gsk-3 to axin , promoting the phosphorylation and degradation of -catenin . activity of the transcription factor , tcf / lef , which forms a complex with -catenin in nucleus , was suppressed by dha in a dose - dependent manner . dha inhibited cox-2 expression and prostaglandin e2 production which mediates cancer cell invasion.32 therefore , dha was suggested as a potential adjuvant in the treatment of cancer . according to deliseo et al.,33 dha inhibited invasion of pt45 pancreatic carcinoma cells by down - modulation of granzyme b expression . granzyme b is a serine protease which is expressed by cytotoxic lymphocytes to induce target cell apoptosis . however , granzyme b is also produced by a variety of normal and neoplastic cells and potentially acts on multiple targets . granzyme b is considered as a powerful regulator of a wide range of fundamental biological processes . tumor - expressed granzyme b degrades ecm components and promotes cancer cell invasion.9 this study is supported by strouch et al.34 who showed that a high 3-fatty acid diet mitigates murine pancreatic precancer development . recent study showed that 3-pufas supplementation reduced circulating pro - angiogenic growth factors , such as pdgf , in the patients with advanced pancreatic cancer.17 spencer et al.26 suggested that dha and epa have potent anti - angiogenic effects by inhibiting production of many important angiogenic mediators namely ; vegf , pdgf , platelet - derived endothelial cell growth factor , cox-2 , prostaglandin e2 , nitric oxide , nf-b , matrix metalloproteinases , and -catenin . they showed that dha and epa have therapeutic potential to inhibit tumor angiogenesis in colon , breast , and prostate cancers . however , there has been little research on the effect of dha on angiogenesis specifically in pancreatic cancer cells . therefore , it is important to determine whether dha has an inhibitory effect on angiogenesis in pancreatic cancer cells , which provide insights into the molecular mechanisms by which dietary dha suppresses the progression of pancreatic cancer . swamy et al.35 found that a synergistic effect was observed on induction of apoptosis ( approximately six - fold ) and inhibition of cell proliferation ( approximately 70% ) when pancreatic cancer ( bxpc-3 ) cells were treated with curcumin together with the dha . a combination of fish oil and curcumin showed a significantly reduced tumor volume in mice . expression and activity of inducible nitric oxide synthase , cox-2 , and 5-lox are down - regulated , and p21 is upregulated in tumor xenograft fed cur - cumin combined with fish oil diet when compared to individual diets . therefore , the combined natural products , such as curcumin and 3-fatty acids , may provide synergistic pancreatic tumor inhibitory properties . previously , we showed that janus kinase / signal transducers and activators of transcription ( jak / stat ) pathway stimulates cell proliferation and malignant transformation and inhibits apoptosis in pancreas.36,37 since dha reduced stat3 activation in human liver cancer ( hepg2 ) cells38 and gastric cancer ( ags ) cells,39 dha may inhibit jak / stat pathway in pancreatic cancer cells . further study should be performed to determine the effect of dha on jak / stat in pancreatic carcinogenesis . because the incidence of and mortality from pancreatic cancer is rising , moreover , dha suppresses expression of pro - angiogenic growth factors , such as vegf and pdgf , preventing cancer cells from getting metabolic requirements and proliferating . further long - term clinical studies are necessary to determine the preventive effect of dha against pancreatic cancer development ( fig .
pancreatic cancer is a highly aggressive malignant tumor of the digestive system and radical resection , which is available to very few patients , might be the only possibility for cure . since therapeutic choices are limited at the advanced stage , prevention is more important for reducing incidence in high - risk individuals with family history of pancreatic cancer . 
 epidemiological studies have shown that a high consumption of fish oil or 3-polyunsaturated fatty acids reduces the risk of pancreatic cancers . 
 dietary fish oil supplementation has shown to suppress pancreatic cancer development in animal models . 
 previous experimental studies revealed that several hallmarks of cancer involved in the pathogenesis of pancreatic cancer , such as the resistance to apoptosis , hyper - proliferation with abnormal wnt/-catenin signaling , expression of pro - angiogenic growth factors , and invasion . 
 docosahexaenoic acid ( dha ) is a 3-polyunsaturated fatty acid and rich in cold oceanic fish oil . 
 dha shows anti - cancer activity by inducing oxidative stress and apoptosis , inhibiting wnt/-catenin signaling , and decreasing extracellular matrix degradation and expression of pro - angiogenic factors in pancreatic cancer cells 
 . this review will summarize anti - cancer mechanism of dha in pancreatic carcinogenesis based on the recent studies .