There is increasing evidence that dietary intake of ω-3 fatty acids suppress progression of breast, prostate and colon cancers.(16
) However, there is limited understanding of how dietary fatty acids may affect the process of pancreatic carcinogenesis and cancer progression. Decreased tumor growth rates in BOP-induced pancreatic cancer were observed in hamsters fed a high ω-3 fat diet.(20
) To date, all of the in vivo
studies regarding the effect of different polyunsaturated fatty acid (PUFA) diets during pancreatic carcinogenesis have utilized carcinogen-induced(7
) and xenograft(24
) models that develop invasive pancreatic cancer. The goal of this study was to assess the possible chemopreventive role of a diet rich in ω-3 fat during the development of precancer in vivo
and determine if this chemopreventive effect was generated by a similar mechanism to that observed in pancreatic cancer cell lines following treatment with an ω-3 fatty acid. To our knowledge, this is the first study to evaluate the effects of an ω-3 fat diet on transgenic mice predisposed to the development of pancreatic precancer.
The most striking finding in this study was the significantly decreased incidence and frequency of pancreatic precancer in EL-Kras F1 mice fed a high ω-3 fat diet versus those fed a standard diet. This change occurred early in the eight-month old mice and persisted in the eleven-month old mice. In addition, the cellular proliferation rate in precancerous lesions was significantly reduced in the ω-3 fatty acid group compared to the standard diet group. Since the Kras mutation is targeted to the acinar compartment, the ω -3 diet likely plays a role in both retarding the transformation process, which leads to the initial formation of pancreatic precancer and then dampering the proliferative ability of the precancerous lesions once they develop. Previous findings in prostate (26
), mammary (27
), skin (28
), and colon(29
) in a precancerous setting demonstrated that administration of high ω-3 diets generated an environment that suppressed tumor establishment. Our results extend this idea into pancreatic precancer development and support previously identified in vivo
effects of high fat diets during pancreatic carcinogenesis but were generated in a precancerous setting in the pancreas. The suppressive nature of an ω-3 fat diet on EL-Kras mice was even more pronounced than those observed in BOP-induced pancreatic cancer in hamsters(20
) since some EL-Kras F1 ω-3 fed mice do not develop precancer.
Two issues remain regarding the phenotypic effects of high PUFA diets on the development of pancreatic precancer in vivo: (1) other potential variables that may contribute to these changes and (2) the mechanisms responsible for cellular/tissue abnormalities leading to precancer. When examining the differences between the high omega-3 and standard diets (see ), the ω-3 fat diet had a higher calorie content per gram than the standard diet. The only means to assess lower fat composition in an isocaloric setting would be to compensate calories from fat with calories from sugar, which changes the whole dynamic of this study from an evaluation of a high dietary omega-3 fat to the source of caloric intake. Even in a proposed isocaloric setting, total calorie intake would be difficult to maintain unless each mouse consumes the same amount of isocaloric diet. Nevertheless, EL-Kras F1 mice fed a high ω-3 fat diet had no significant difference in body weights compared to mice fed a control diet. Moreover, our in vitro data demontrating a lower proliferation rate in pancreatic cancer cells treated with DHA supports our in vivo findings and implicates the ω-3 fat as the main factor associated the proliferative changes and precancer inhibition. Furthermore, we demonstrated that DHA affects proliferation through both induction of G1 arrest and apoptosis.
In conclusion, we demonstrated for the first time, that a diet high in ω-3 fat may mitigate the development of pancreatic precancer. Omega-3 fats appear to have this effect by inhibiting pancreatic lesion proliferation through induction of G1 cell cycle arrest and apoptosis. More work is needed to further elucidate the mechanisms of action of ω-3 fatty acids and is the focus of our next study. The present study serves as provocative preclinical data that dietary intake of omega-3 fat may mitigate the development of pancreatic precancer or cancer in high-risk pancreatic cancer kindreds. Likely, the most effective method to alter a patient's intake of omega-3 fat would be in the form of vitamin supplementation (fish oil, flax seed oil etc.). Ultimately, a high ω-3 fat diet may hold promise as a means of impeding the development and progression of pancreatic precancer.