Despite progress made in other epithelial malignancies, pancreatic cancer still remains an almost universally ethal disease with an overall median survival of less than 6 months. The current understanding of risk factors leading to the development of invasive pancreatic cancers mostly stem from epidemiologic observations. There is strong evidence that caloric excess with ensuing obesity increases the risk of developing pancreatic cancer. Although epidemiological data regarding dietary fat intake and pancreatic cancer risk are inconsistent, preclinical models convincingly suggest a positive relationship. Biochemical analyses have shown that saturated fatty acids and n-6 polyunsaturated fatty acids may be associated with an increased cancer risk, while n-3 polyunsaturated fatty acids, found in marine fish, may have protective properties. Additionally, n-3 polyunsaturated fatty acids seem to inhibit the growth of established cancers. It is well accepted today that invasive pancreatic adenocarcinomas arise from non-invasive precursor lesions, called pancreatic intraepithelial neoplasias (PanlNs). The present application tests the hypothesis that dietary n-3 polyunsaturated fatty acids lower the risk of developing pancreatic cancer (preventive effect) and reduce the growth and spread of established pancreatic cancer (therapeutic effect). The proposed studies are designed 1) to determine the effect of polyunsaturated fatty acids on pancreatic cancer cell growth in vitro and to understand the underlying mechanisms, 2) to determine the therapeutic role of dietary polyunsaturated fatty acids on pancreatic cancer growth and recurrence in vivo using xenograft animal models, and 3) to evaluate the preventive effect of polyunsaturated fatty acids on the development and progression of PanlNs using a transgenic animal model. The effects of polyunsaturated fatty acids on membrane fatty acid composition and eicosanoid production will be measured by gas chromatography/mass spectroscopy. The effects of polyunsaturated fatty acids on pancreatic cancer cell growth and the underlying signaling pathways will be characterized. Mice will be fed with various diets, which differ in their ratio of n-6 and n-3 fatty acids. The effect on the growth and recurrence of established pancreatic cancer as well as on the development and progression of PanlNs will be determined. The proposed studies will help to understand the epidemiologic data on dietary fat and pancreatic cancer and will provide the scientific rationale for future dietary recommendations on pancreatic cancer prevention emphasizing the benefits of fish as part of a healthy diet. The proposed experiments will help to develop a feasible biomarker of dietary fatty acid intake, which can be used in future cancer prevention trials, and to design clinical trials, which test n-3 fatty acids as novel therapeutic agents in patients with unresectable pancreatic cancer or as part of an adjuvant regimen after primary tumor resection to reduce tumor recurrences. ? ? ?
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