Obesity and Pancreatic Cancer: The Role of IGF-1

在过去的30年里，肥胖在美国急剧增加，并且与胰腺炎和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）。IGF-1也被证明是卡路里限制（CR）的抗癌作用的主要中介，在许多模型系统中是一种有效的抗肥胖和癌症预防干预。假设肥胖会通过激活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，进而增强增殖和炎症。这一假设将在一种新的胰腺炎/胰腺腺癌模型中得到验证，这是一种角蛋白5 （K5）驱动的环氧化酶2 （COX-2）转基因小鼠，称为K5.COX-2。在该模型中，100%的小鼠在6个月后发展为胰腺炎并发展为胰腺腺癌。这个模型是相关的，因为COX-2在人类胰腺炎和胰腺腺癌中上调。目的1将侧重于确定饮食能量平衡对胰腺病变发展的影响，并在肥胖小鼠中证明IGF-1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小鼠也将与肝脏特异性表达缺乏IGF-1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肿瘤的影响。Aim 2中的研究将确定诱导肥胖的饮食在多大程度上增强和抑制炎症（循环细胞因子水平和炎症细胞浸润），IGF-1对炎症的贡献，以及炎症对胰腺肿瘤发生的贡献。为了确定细胞因子对胰腺肿瘤发生的重要性，将给K5施用细胞因子合成抑制剂己酮茶碱。COX-2小鼠在CR，正常或肥胖诱导饮食。为了确定IGF-1是否单独诱导炎症，K5。正常或CR饮食的COX-2小鼠将被给予IGF-1，并评估循环细胞因子和炎症细胞浸润。Aim 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丝裂原，IGF-1和胰岛素的信号通路，以及能量平衡是否影响IGF-1或胰岛素受体的表达。Aim 4的重点是确定抑制IGF-1R信号的PI3-K/mTOR通路和/或MAPK通路是否会减少肥胖诱导的胰腺癌。这将通过将Akt抑制剂Rad001和/或MAPK抑制剂Cl-0140施用于K5来完成。COX-2小鼠和评估病变发展，炎症细胞浸润和增殖标志物。本提案的总体目标是确定肥胖如何促进胰腺癌的发展，并确定降低肥胖对胰腺癌影响的分子靶点。公共卫生相关性：提出的研究应提供关于肥胖如何促进胰腺癌发展的新信息。这些信息在设计方法或治疗方法时应该是有用的，这些方法或治疗方法将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.