Omega-3 Fatty Acid Effects on Pancreatitis and Adenocarcinoma Development

描述(申请人提供)：胰腺癌是美国癌症死亡的第四大原因。五年存活率只有5%，因为没有诊断标记物可用于早期检测。炎症已成为包括胰腺癌在内的多种癌症发生的重要危险因素。我们假设，用鱼油中发现的抗炎omega-3多不饱和脂肪酸(PUFAs)抑制炎症将抑制炎症和随后的胰腺癌发展。为了验证这一假设，我们将使用环氧合酶2(COX-2)转基因小鼠模型，在胰腺炎发作之前喂食富含omega-3脂肪酸二十碳五烯酸(EPA)或omega-6脂肪酸亚油酸的食物。COX-2转基因小鼠过表达COX-2基因，导致自发性胰腺炎和随后发生的胰腺癌。这一模型具有很高的相关性，因为COX-2在人类胰腺炎和胰腺癌中高表达。将对胰腺进行组织病理学检查，以确定饮食EPA是否抑制免疫细胞招募和随后的胰腺炎导致腺癌的发展。还将进行胰腺中细胞因子基因表达和引流淋巴结中T细胞亚群的分析，以确定EPA的有益作用是否与调节先天免疫或获得性免疫有关，或两者兼而有之。还将对胰腺中前列腺素的产生和脂肪酸组成进行脂质分析，以评估这些脂质变化如何与胰腺炎的变化相关。发现omega-3PUFAs抑制炎症的新免疫靶点将为提出其他有针对性的实验提供必要的数据，旨在阐明omega-3PUFAs和炎症调控胰腺癌发展的免疫机制(S)。这一数据可能表明，omega-3多不饱和脂肪酸，尤其是EPA，在癌症预防中发挥了重要作用，因为它们是众所周知的抗炎药，在美国人中被广泛消费。 公共卫生相关性：胰腺癌是癌症死亡的第四大原因，由于缺乏早期检测技术，五年存活率为5%。慢性炎症与许多不同疾病的病因有关，包括胰腺癌。我们认为，饮食中的omega-3多不饱和脂肪酸可能有助于延缓胰腺炎的发生，并延缓胰腺癌的早期发展。这个项目与公众健康相关，因为它将为延缓胰腺癌发展的新饮食策略提供证据。

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.