Obesity and Pancreatic Cancer: The Role of IGF-1

肥胖和胰腺癌：IGF-1 的作用

基本信息

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
项目类别：
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

项目摘要

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 - IGF-1 (IGF-1) 也被证明是热量限制 (CR) 抗癌作用的主要介质，在许多方面是一种有效的抗肥胖和癌症预防干预措施。假设肥胖会通过激活 IGF-1 途径增强胰腺炎和胰腺病变，从而增强增殖和炎症，这一假设将在胰腺炎/胰腺的新模型中得到检验。角蛋白 5 (K5) 驱动的环氧合酶 2 (COX-2) 转基因小鼠，称为 K5.COX-2，在该模型中，100% 的小鼠发生腺癌。 6 个月时进展为胰腺腺癌的胰腺炎该模型具有相关性，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平衡对胰腺病变发展的影响，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，并确定IGF-1水平降低对肥胖诱导的胰腺瘤形成的影响。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，以及炎症对炎症发展的贡献。胰腺肿瘤发生。为了确定细胞因子对胰腺肿瘤发生的重要性，将细胞因子合成抑制剂己酮可可碱给予CR、正常或肥胖诱导饮食的K5.COX-2小鼠。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并评估循环细胞因子和炎症细胞浸润。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 的重点是确定抑制 IGF-1R 信号传导的 PI3-K/mTOR 通路和/或 MAPK 通路是否会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。