Inflammatory processes In diet-Induced pancreatic cancer promotion

饮食诱发的胰腺癌促进中的炎症过程

• 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
• 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

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.

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的发展，包括癌症。尽管潜在的机制 可能是多方面的，炎症当然在高脂肪饮食引起的肥胖中起着重要作用， 癌浸润的炎性细胞以及全身和局部促炎介质水平 为肿瘤发展提供理想的微环境抗炎策略已在许多 延迟或预防癌症发展的动物模型， 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）在炎症微环境的存在下， 和胰腺癌前体病变的进展， 此外，我们先前发表的研究表明， 抗炎药的给药延迟了胰腺癌前体病变的进展， 胰腺癌发展的条件性Kras小鼠模型。此外，膳食补充剂 鱼油在异种移植小鼠模型中抑制胰腺癌生长， 促炎前列腺素的水平。本项目的首要假设是， 促进胰腺癌的发展和生长。这种效应是由 一个炎症微环境。靶向炎症反应可以预防胰腺癌 由HFCD推动的发展。为了验证我们的假设，提出了以下三个具体目标。 1)确定胰腺炎症在HFCD诱导的胰腺癌中的重要性 2）描述类二十烷酸在HFCD诱导的胰腺癌中的重要性 开发和研究其机制，和3）确定鱼油作为抗- 炎症策略，以减少胰腺癌的发展。最先进的基因工程 将利用动物模型来检验假设。在细胞培养中将剖析潜在的机制 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，显著延缓或预防高脂肪、高热量饮食的促肿瘤作用。 由于今天鱼油被广泛用作一般健康促进膳食补充剂，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 研究结果也可用于其他与肥胖有关的癌症，甚至非恶性慢性疾病。