Obesity and Pancreatic Cancer: The Role of IGF-1

肥胖和胰腺癌：IGF-1 的作用

• 批准号: 8259466
• 负责人: SUSAN M FISCHER
• 金额: $ 31.98万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259466
• 关键词: Affect; Biological Models; C57BL/6 Mouse; Caloric Restriction; Carcinogens; Cell Line; Cell Proliferation; Cells; Connective Tissue; Development; Diet; Fibrosis; Goals; Health; 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; PTGS2 gene; Pancreas; Pancreatic Adenocarcinoma; Pancreatitis; Pathway interactions; Pentoxifylline; Phenotype; Predisposition; Preventive Intervention; Proliferation Marker; Reporting; Role; Serum; Signal Pathway; Signal Transduction; Skin; Skin Neoplasms; Somatomedins; TNF gene; Testing; Tissues; Transgenic Mice; Tumor Cell Line; Tumor Promoters; 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 cancer cells; pancreatic neoplasm; pancreatic tumorigenesis; 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：在过去30年中，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相关。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也被证明是热量限制（CR）抗癌作用的主要介质，在许多模型系统中是一种有效的抗肥胖和癌症预防干预。据推测，肥胖将通过激活IGF-1途径增强胰腺炎和胰腺病变，而CR将通过激活IGF-1途径抑制胰腺炎和胰腺病变，IGF-1途径随后增强增殖和炎症。将在胰腺炎/胰腺癌的新模型中检验该假设，所述模型是角蛋白5（K5）驱动的环氧合酶-2（考克斯-2）转基因小鼠，称为K5.考克斯-2。在该模型中，100%的小鼠发生胰腺炎，并在6个月时进展为胰腺癌。该模型是相关的，因为考克斯-2在人胰腺炎和胰腺癌中上调。目标1将集中于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。将给K5.COX-2小鼠喂食导致瘦、超重和肥胖表型的饮食，并评估胰腺病变的程度和类型。还将K5.COX-2小鼠与IGF- 1肝脏特异性表达缺陷的小鼠（LID转基因小鼠）杂交，并测定降低的IGF-1水平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性细胞浸润）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。为了确定细胞因子对胰腺肿瘤发生的重要性，将细胞因子合成的抑制剂喷替福林给予CR、正常或诱导肥胖饮食的K5.COX-2小鼠。为了确定单独的IGF-1是否诱导炎症，对正常或CR饮食的K5.C0X-2小鼠施用IGF-1并评估循环细胞因子和炎性细胞浸润。目的3将测试IGF-1、胰岛素或细胞因子TNF 1或IL-12是否是胰腺肿瘤细胞中的直接有丝分裂原、IGF-1和胰岛素信号传导的途径以及能量平衡是否影响IGF-1或胰岛素受体表达。目的4集中于确定抑制IGF-1 R信号传导的PI 3-K/mTOR通路和/或MAPK通路是否会减少肥胖诱导的胰腺癌。这将通过向K5.COX-2小鼠施用Akt抑制剂Rad 001和/或MAPK抑制剂Cl-0140并评估病变发展、炎性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。

项目成果

Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms.

• DOI: 10.2337/db14-1132
• 发表时间: 2015-05
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Cifarelli V;Lashinger LM;Devlin KL;Dunlap SM;Huang J;Kaaks R;Pollak MN;Hursting SD
• 通讯作者: Hursting SD

Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity.

• DOI: 10.1530/erc-11-0213
• 发表时间: 2012-02
• 期刊: Endocrine-related cancer
• 影响因子: 3.9
• 作者: Leticia M. Nogueira;Sarah M. Dunlap;Nikki A. Ford;S. Hursting