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。五年生存率只有5%，因为没有早期检测的诊断标志物。炎症已成为包括胰腺癌在内的许多类型癌症发展的重要风险因素。我们假设用鱼油中的抗炎性ω-3多不饱和脂肪酸（PUFA）抑制炎症将抑制炎症和随后的胰腺癌发展。为了检验这一假设，我们将使用环加氧酶2（考克斯-2）转基因小鼠模型，在胰腺炎发作之前喂食富含ω-3脂肪酸二十碳五烯酸（EPA）或ω-6脂肪酸亚油酸的饮食。考克斯-2 Tg小鼠过表达考克斯-2基因，其引起自发性胰腺炎和随后的胰腺腺癌的发展。该模型是高度相关的，因为在人胰腺炎和胰腺癌中发现高考克斯-2表达。将对胰腺进行组织学检查，以确定饮食EPA是否抑制免疫细胞募集和随后的胰腺炎，从而导致腺癌的发展。还将进行胰腺中的细胞因子基因表达和引流淋巴结中的T细胞亚群分析，以确定EPA的有益作用是否与先天性或适应性免疫或两者的调节有关。还将对胰腺的前列腺素类产生和脂肪酸组成进行脂质组学分析，以评价这些脂质变化如何与胰腺炎的变化相关。确定通过ω-3 PUFA抑制炎症的新免疫靶点将提供必要的数据，以提出旨在阐明ω-3 PUFA和炎症调节胰腺癌发展的免疫机制的额外集中实验。这些数据可能表明omega-3 PUFA，特别是EPA在癌症预防中的重要作用，因为它们是众所周知的抗炎剂，并且被美国人广泛消费。

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.