Omega-3 Fatty Acid Effects on Pancreatitis and Adenocarcinoma Development

描述（由申请人提供）：胰腺癌是美国癌症死亡的第四大原因。由于没有可用于早期检测的诊断标记物，5年生存率仅为5%。炎症已成为包括胰腺癌在内的多种癌症发展的重要危险因素。我们假设，用鱼油中发现的抗炎-3多不饱和脂肪酸（PUFAs）抑制炎症会抑制炎症和随后的胰腺腺癌发展。为了验证这一假设，我们将使用环加氧酶2 （COX-2）转基因小鼠模型，在胰腺炎发病前喂食富含omega-3脂肪酸二十碳五烯酸（EPA）或omega-6脂肪酸亚油酸的饲料。COX-2 Tg小鼠过度表达导致自发性胰腺炎和随后发展为胰腺腺癌的COX-2基因。这个模型是高度相关的，因为在人类胰腺炎和胰腺癌中发现了高COX-2表达。将进行胰腺组织病理学检查，以确定饮食EPA是否抑制免疫细胞募集和随后导致腺癌发展的胰腺炎。还将进行胰腺细胞因子基因表达和引流淋巴结T细胞亚群分析，以确定EPA的有益作用是否与先天免疫或适应性免疫的调节有关，或两者兼有。脂质组学分析也将用于胰脏的前列腺素生成和脂肪酸组成，以评估这些脂质变化如何与胰腺炎的改变相关。确定通过omega-3 PUFAs抑制炎症的新免疫靶点将为提出旨在阐明omega-3 PUFAs和炎症调节胰腺癌发展的免疫机制的额外重点实验提供必要的数据。这些数据可能表明omega-3 PUFAs，尤其是EPA，在预防癌症方面发挥着重要作用，因为它们是众所周知的抗炎剂，在美国被广泛食用。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer death in the United States. The five- year survival rate is only 5% because no diagnostic markers are available for early detection. Inflammation has emerged as an important risk factor for the development of many types of cancers including pancreatic cancer. We hypothesize that suppressing inflammation with the anti-inflammatory omega-3 polyunsaturated fatty acids (PUFAs) found in fish oil will suppress inflammation and subsequent pancreatic adenocarcinoma development. To test this hypothesis, we will use the cyclooxygenase 2 (COX-2) transgenic mouse model fed diets enriched in either the omega-3 fatty acid eicosapentaenoic acid (EPA) or the omega-6 fatty acid linoleic acid prior to the onset of pancreatitis. The COX-2 Tg mouse overexpresses the COX-2 gene which causes spontaneous pancreatitis and subsequent development of pancreatic adenocarcinomas. This model is highly relevant because high COX-2 expression is found in human pancreatitis and pancreatic cancer. Histopathological examination of the pancreata will be performed to determine if dietary EPA suppresses immune cell recruitment and subsequent pancreatitis leading to adenocarcinoma development. Cytokine gene expression in the pancreata and T cell subset analysis in draining lymph nodes will also be performed to establish whether the beneficial effects of EPA are linked to modulation of innate or adaptive immunity or both. Lipodomic analysis will also be carried out for prostanoid production and fatty acid composition of the pancreata to evaluate how these lipid changes correlate with alterations in pancreatitis. Identifying novel immune targets of suppressing inflammation by omega-3 PUFAs will provide the necessary data to propose additional focused experiments aimed at elucidating the immune mechanism(s) by which omega-3 PUFAs and inflammation regulate pancreatic cancer development. This data may show an important role for the omega-3 PUFAs, especially EPA, in cancer prevention because they are well known anti-inflammatory agents and are widely consumed by people in the United States. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer death and has a 5% five-year survival rate due to lack of early detection techniques. Chronic inflammation is linked to the etiology of many different diseases, including pancreatic cancer. We propose that dietary omega-3 PUFAs may help delay the onset of pancreatitis and slow the early stages of pancreatic cancer development. This project is relevant to public health because it will provide evidence for a new dietary strategy to delay the development of pancreatic cancer.