Obesity and Pancreatic Cancer: The Role of IGF-1

描述(申请人提供：在过去的30年里，肥胖在美国急剧增加，并与胰腺炎、胰腺癌以及其他癌症有关。肥胖和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)。在许多模型系统中，IGF-1也被证明是卡路里限制(CR)抗癌效果的主要介体，CR是一种有效的抗肥胖和癌症预防措施。据推测，肥胖会增加，CR会通过激活IGF-1途径抑制胰腺炎和胰腺病变，从而促进增殖和炎症。这一假设将在一种新的胰腺炎/胰腺癌模型中得到验证，这是一种角蛋白5(K5)驱动的环氧合酶-2(COX-2)转基因小鼠，被称为K5.COX-2。在这个模型中，100%的小鼠发生胰腺炎，并在6个月后进展为胰腺癌。这个模型是相关的，因为COX-2在人类胰腺炎和胰腺癌中上调。目的1将着重于确定饮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小鼠将被喂养导致瘦、超重和肥胖表型的饮食，并评估胰腺损伤的范围和类型。K5.COX-2小鼠还将与肝脏特异表达IGF-1的小鼠(LID转基因小鼠)杂交，以确定IGF-1水平降低对肥胖诱导的胰腺肿瘤的影响。Aim 2中的研究将确定肥胖饮食在多大程度上促进和抑制炎症(循环细胞因子水平和炎性细胞浸润)，IGF-1对炎症的贡献，以及炎症对胰腺肿瘤发生发展的贡献。为了确定细胞因子在胰腺肿瘤发生中的重要性，细胞因子合成的抑制剂己酮可可碱将被给予K5.COX-2小鼠CR、正常或肥胖诱导饮食。为了确定IGF-1是否单独引起炎症，K5COX-2小鼠在正常或CR饮食中被给予IGF-1，并评估循环中的细胞因子和炎症细胞的浸润。目的研究胰岛素样生长因子-1、胰岛素、细胞因子TNF1、IL-12是否是胰腺肿瘤细胞的直接有丝分裂原，胰岛素样生长因子-1与胰岛素信号传导途径(S)以及能量平衡是否影响胰岛素样生长因子-1或胰岛素受体的表达。目的4的重点是确定抑制PI3-K/mTOR通路和/或IGF-1R信号的MAPK通路是否会减少肥胖诱导的胰腺癌。这将通过给K5.COX-2小鼠注射Akt抑制剂RAD001和/或MAPK抑制剂CL-0140，并评估病变发展、炎症细胞渗透和增殖标志来实现。这项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：建议的研究应该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。

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.