The role of n-3 polyunsaturated fatty acids in pancreatic cancer

描述（由申请人提供）：尽管在其他上皮恶性肿瘤方面取得了进展，但胰腺癌仍然是一种几乎普遍致死的疾病，总体中位生存期不到6个月。目前对导致侵袭性胰腺癌发展的危险因素的理解主要来自流行病学观察。有强有力的证据表明，热量过剩与随之而来的肥胖增加了患胰腺癌的风险。虽然关于膳食脂肪摄入和胰腺癌风险的流行病学数据不一致，但临床前模型令人信服地表明了正相关关系。生化分析表明，饱和脂肪酸和n-6多不饱和脂肪酸可能与癌症风险增加有关，而在海洋鱼类中发现的n-3多不饱和脂肪酸可能具有保护作用。此外，n-3多不饱和脂肪酸似乎可以抑制已建立的癌症的生长。目前公认的是，侵袭性胰腺腺癌起源于非侵袭性前驱病变，称为胰腺上皮内瘤形成（PanIN）。本申请测试了膳食n-3多不饱和脂肪酸降低发生胰腺癌的风险（预防作用）和减少已建立的胰腺癌的生长和扩散（治疗作用）的假设。所提出的研究被设计为1）确定多不饱和脂肪酸对胰腺癌细胞体外生长的影响并理解潜在的机制，2）使用异种移植动物模型确定膳食多不饱和脂肪酸对胰腺癌生长和体内复发的治疗作用，和3）使用转基因动物模型评估多不饱和脂肪酸对PanIN的发展和进展的预防作用。多不饱和脂肪酸对膜脂肪酸组成和类二十烷酸产生的影响将通过气相色谱/质谱法测量。多不饱和脂肪酸对胰腺癌细胞生长的影响和潜在的信号通路将被表征。小鼠将被喂食各种饮食，其n-6和n-3脂肪酸的比例不同。将确定对已建立的胰腺癌的生长和复发以及对PanIN的发展和进展的影响。拟议的研究将有助于了解膳食脂肪和胰腺癌的流行病学数据，并将为未来预防胰腺癌的饮食建议提供科学依据，强调鱼类作为健康饮食的一部分的益处。拟议的实验将有助于开发一种可行的膳食脂肪酸摄入生物标志物，可用于未来的癌症预防试验，并设计临床试验，测试n-3脂肪酸作为不可切除的胰腺癌患者的新型治疗药物，或作为原发性肿瘤切除术后辅助治疗方案的一部分，以减少肿瘤复发。

DESCRIPTION (provided by applicant): 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.