Obesity and Pancreatic Cancer: The Role of IGF-1

肥胖和胰腺癌：IGF-1 的作用

• 批准号: 7653538
• 负责人: SUSAN M FISCHER
• 金额: $ 34.34万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-07 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653538
• 关键词: Affect; Biological Models; C57BL/6 Mouse; Caloric Restriction; Carcinogens; Cell Line; Cell Proliferation; Cells; Connective Tissue; Development; Diet; Fibrosis; Goals; Human; Incidence; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Interleukin-12; Knock-out; Lesion; Link; Liver; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediator of activation protein; Mitogen-Activated Protein Kinase Inhibitor; Mitogens; Modeling; Molecular Target; Mus; Obese Mice; Obesity; Overweight; Pancreas; Pancreatic Adenocarcinoma; Pancreatitis; Pathway interactions; Pentoxifylline; Phenotype; Predisposition; Preventive Intervention; Proliferation Marker; Reporting; Role; Serum; Signal Pathway; Signal Transduction; Skin; Skin Neoplasms; Somatomedins; Testing; Tissues; Transgenic Mice; Tumor Cell Line; Tumor Promoters; cancer cell; chronic pancreatitis; cyclooxygenase 2; cytokine; design; dietary restriction; energy balance; feeding; human FRAP1 protein; human disease; inhibitor/antagonist; insulin signaling; keratin 5; mTOR Inhibitor; neoplastic cell; overexpression; pancreatic neoplasm; pancreatic tumorigenesis; public health relevance; receptor; receptor expression; response; tumorigenic

DESCRIPTION (provided by applicant: Obesity has increased dramatically over the past 30 years in the USA and has been associated with pancreatitis and pancreatic cancer, as well as other cancers. A potential mechanistic link between obesity and cancer susceptibility is insulin-like growth factor-1 (IGF-1). IGF-1 has also been shown to be a principal mediator of the anti-cancer effects of calorie restriction (CR), a potent anti-obesity and cancer preventive intervention in a number of model systems. It is hypothesized that obesity will enhance, and CR will inhibit, pancreatitis and pancreatic lesions via activation of the IGF-1 pathway, which subsequently enhances proliferation and inflammation. This hypothesis will be tested in a new model of pancreatitis/pancreatic adenocarcinoma, a keratin 5 (K5)-driven cyclooxygenase-2 (COX-2) transgenic mouse, referred to as K5.COX-2. In this model,100% of the mice develop pancreatitis that progresses to pancreatic adenocarcinoma by 6 months. This model is relevant because COX-2 is upregulated in human pancreatitis and pancreatic adenocarcinoma. Aim 1 will focus on determining the effects of dietary energy balance on the development of pancreatic lesions and demonstrating a causal role for IGF-1 in obese mice. K5.COX-2 mice will be fed diets that result in lean, overweight and obese phenotypes and assessed for extent and type of pancreatic lesions. K5.COX-2 mice will also be crossed with mice deficient in liver-specific expression of IGF- 1 (LID transgenic mice) and the effect of reduced IGF-1 levels on obesity-induced pancreatic neoplasia determined. The studies in Aim 2 will determine the extent to which obesity-inducing diets enhance, and CR inhibits, inflammation (circulating cytokine levels and inflammatory cell infiltration), the contribution of IGF-1 to inflammation, and the contribution of inflammation to the development of pancreatic tumorigenesis. To determine the importance of cytokines to pancreatic tumorigenesis, an inhibitor of cytokine synthesis, pentoxifylline, will be administered to K5.COX-2 mice on CR, normal or obesity-inducing diets. To determine whether IGF-1 alone induces inflammation, K5.COX-2 mice on normal or CR diets will be administered IGF-1 and circulating cytokines and inflammatory cell infiltration assessed. Aim 3 will test whether IGF-1, insulin, or the cytokines TNF1 or IL-12, are direct mitogens in pancreatic tumor cells, the pathway(s) by which IGF-1 and insulin signal and whether energy balance affects IGF-1 or insulin receptor expression. Aim 4 is focused on determining whether inhibition of either the PI3-K/mTOR pathway and/or the MAPK pathway of IGF-1R signaling will reduce obesity-induced pancreatic cancer. This will be done by administering either the Akt inhibitor Rad001 and/ or the MAPK inhibitor Cl-0140 to K5.COX-2 mice and assessing lesion development, inflammatory cell infiltration and markers of proliferation. The overall goal of this proposal is to determine how obesity enhances pancreatic cancer development and to identify molecular targets that reduce the effect of obesity on pancreatic cancer. PUBLIC HEALTH RELEVANCE: The studies proposed should provide new information on how obesity contributes to the development of pancreatic cancer. This information should be useful in designing approaches or treatments that will counteract the effect of obesity on this very fatal human disease.

描述（由申请人提供：过去 30 年来，美国肥胖人数急剧增加，并且与胰腺炎、胰腺癌以及其他癌症有关。肥胖与癌症易感性之间的潜在机制联系是胰岛素样生长因子-1 (IGF-1)。IGF-1 也已被证明是热量限制 (CR) 抗癌作用的主要介质，而热量限制是一种有效的抗癌作用。 一些模型系统中的抗肥胖和癌症预防干预。据推测，肥胖会通过激活 IGF-1 途径增强胰腺炎和胰腺病变，而 CR 会抑制胰腺炎和胰腺病变，从而增强增殖和炎症。这一假设将在一种新的胰腺炎/胰腺癌模型（角蛋白 5）中得到检验。 (K5)驱动的环氧合酶2(COX-2)转基因小鼠，简称K5.COX-2。在该模型中，100% 的小鼠患上胰腺炎，并在 6 个月内进展为胰腺腺癌。该模型具有相关性，因为 COX-2 在人类胰腺炎和胰腺腺癌中表达上调。目标 1 将重点确定膳食能量的影响 胰腺损伤发展的平衡并证明 IGF-1 在肥胖小鼠中的因果作用。 K5.COX-2 小鼠将被喂食导致瘦、超重和肥胖表型的饮食，并评估胰腺病变的程度和类型。 K5.COX-2小鼠还将与肝脏特异性IGF-1表达缺陷的小鼠（LID转基因小鼠）杂交，效果 确定IGF-1水平降低对肥胖引起的胰腺肿瘤的影响。目标 2 中的研究将确定肥胖诱导饮食增强和 CR 抑制炎症（循环细胞因子水平和炎症细胞浸润）的程度、IGF-1 对炎症的贡献以及炎症对胰腺肿瘤发生发展的贡献。确定 为了了解细胞因子对胰腺肿瘤发生的重要性，将向接受 CR、正常或肥胖诱导饮食的 K5.COX-2 小鼠施用细胞因子合成抑制剂己酮可可碱。为了确定 IGF-1 是否单独诱导炎症，对正常或 CR 饮食的 K5.COX-2 小鼠施用 IGF-1 以及循环细胞因子和炎症细胞 渗透评估。目标 3 将测试 IGF-1、胰岛素或细胞因子 TNF1 或 IL-12 是否是胰腺肿瘤细胞中的直接有丝分裂原、IGF-1 和胰岛素信号传导途径以及能量平衡是否影响 IGF-1 或胰岛素受体表达。目标 4 的重点是确定是否抑制 PI3-K/mTOR 通路和/或 MAPK 通路的 IGF-1R 信号传导将减少肥胖诱发的胰腺癌。这将通过向 K5.COX-2 小鼠施用 Akt 抑制剂 Rad001 和/或 MAPK 抑制剂 Cl-0140 并评估病变发展、炎症细胞浸润和增殖标志物来完成。该提案的总体目标是确定肥胖如何促进胰腺癌的发展并 确定减少肥胖对胰腺癌影响的分子靶点。公共卫生相关性：拟议的研究应提供有关肥胖如何促进胰腺癌发展的新信息。这些信息应该有助于设计方法或治疗方法，以抵消肥胖对这种非常致命的人类疾病的影响。