Inflammatory processes In diet-Induced pancreatic cancer promotion

饮食诱发的胰腺癌促进中的炎症过程

基本信息

批准号：
8561427
负责人：
Guido Erwin Michael Eibl
金额：
$ 20.08万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8561427
关键词：
Animal Feed Animal Model Anti-Inflammatory Agents Anti-inflammatory Calories Cell Culture System Cells Chronic Disease Development Diet Dietary Supplementation Dinoprostone Disease Dose Economics Eicosanoids Environment Fatty acid glycerol esters Fish Oils Genetic Engineering Growth Growth and Development function Health Histologic In Vitro Incidence Inflammation Inflammation Mediators Inflammatory Inflammatory Infiltrate Inflammatory Response Instruction Lesion Malignant Neoplasms Malignant neoplasm of pancreas Mediating Non-Malignant Obesity Obesity associated cancer Oils Omega-3 Fatty Acids Oral Administration Outcome Pancreas Pancreatic Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pharmaceutical Preparations Play Process Prostaglandins Publishing Research Personnel Role Signal Pathway Societies Staging Testing Transgenic Mice Xenograft procedure cancer prevention dietary supplements feeding macrophage mouse model prevent programs receptor tumor

项目摘要

There is substantial evidence that the Western-style diet, rich in fats and calories, is a critical factor in the development of obesity and other chronic diseases, including cancer. Although the underlying mechanisms are likely multi-faceted, inflammation certainly plays an important role in High Fat Diet-induced obesity and cancer. Infiltrating inflammatory cells as well as systemic and local levels of pro-inflammatory mediators provide in ideal micro-milieu for tumor development Anti-inflammatory strategies have been shown in many animal models to delay or prevent the development of cancers and are widely considered intriguing approaches for cancer prevention. Our preliminary studies have shown that a high fat, high calorie diet (HFCD) in the presence of an inflammatory micro-environment substantially accelerates the development and progression of pancreatic cancer precursor lesions in a genetically engineered animal model of pancreatic cancer development Furthermore, our previous published studies have demonstrated that oral administration of an anti-inflammatory drug delays the progression of pancreatic cancer precursor lesions in the conditional Kras mouse model of pancreatic cancer development. In addition, dietary supplementation of fish oil inhibited pancreatic cancer grov\rth in a xenograft mouse model, which was accompanied by reduced levels of pro-inflammatory prostaglandin species. The overarching hypothesis of this Project is that a HFCD promotes pancreatic cancer development and growth. This effect mediated and accelerated by the presence of an inflammatory micro-environment. Targeting the inflammatory response may prevent pancreatic cancer development promoted by the HFCD. To test our hypothesis the following three Specific Aims are proposed. 1) To determine the importance of pancreatic inflammation in HFCD-induced pancreatic cancer development, 2) to characterize the importance of eicosanoids in HFCD-induced pancreatic cancer development and investigate their mechanisms, and 3) to determine the efficacy of fish oil as an anti- inflammatory strategy to reduce pancreatic cancer development. State-of-the-art genetically engineered animal models will be utilized to test the hypotheses. Underlying mechanisms will be dissected in cell culture systems that mimic the different stages of pancreatic cancer development. RELEVANCE (See instructions): We anticipate proving our hypothesis that strategies aimed at inhibiting the inflammatory component, e.g. through fish oil, significantly delay or prevent the tumor-promoting effects of the high fat, high calohe diet. Since today fish oil is widely used as a general health-promoting dietary supplement, our studies will provide the scientific rationale for the use of fish oil to prevent pancreatic cancer and elucidate its mechanism. Our results may also be transferable to other obesity-related cancer and even non-malignant chronic diseases.

有大量证据表明，富含脂肪和热量的西式饮食是导致肥胖的关键因素。肥胖和其他慢性疾病（包括癌症）的发展。尽管底层机制可能是多方面的，炎症肯定在高脂肪饮食引起的肥胖中起着重要作用，癌症。浸润炎症细胞以及全身和局部水平的促炎介质为肿瘤的发展提供理想的微环境抗炎策略已在许多研究中得到证实延迟或预防癌症发展的动物模型被广泛认为是有趣的预防癌症的方法。我们的初步研究表明，高脂肪、高热量饮食 (HFCD) 在存在炎症微环境的情况下大大加速了发展基因工程动物模型中胰腺癌前体病变的进展和进展此外，我们之前发表的研究表明，口服抗炎药的施用可延缓胰腺癌前驱病变的进展胰腺癌发展的条件 Kras 小鼠模型。另外，饮食上补充鱼油在异种移植小鼠模型中抑制胰腺癌的生长，同时伴随着促炎性前列腺素的水平。该项目的总体假设是 HFCD 促进胰腺癌的发展和生长。这种效应是由存在介导和加速的炎症微环境。针对炎症反应可以预防胰腺癌 HFCD 推动的发展。为了检验我们的假设，提出了以下三个具体目标。 1) 确定胰腺炎症在 HFCD 诱发的胰腺癌中的重要性开发，2) 表征类二十烷酸在 HFCD 诱发的胰腺癌中的重要性开发并研究其机制，以及3）确定鱼油作为抗- 减少胰腺癌发展的炎症策略。最先进的基因工程将利用动物模型来检验假设。将在细胞培养中剖析潜在机制模拟胰腺癌发展不同阶段的系统。相关性（参见说明）：我们期望证明我们的假设，即旨在抑制炎症成分的策略，例如通过鱼油，可以显着延缓或阻止高脂肪、高热量饮食的促肿瘤作用。由于今天鱼油被广泛用作一般促进健康的膳食补充剂，我们的研究将提供使用鱼油预防胰腺癌的科学原理并阐明其机制。我们的结果也可能适用于其他与肥胖相关的癌症，甚至非恶性慢性疾病。