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.

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）驱动的环氧酶-2（COX-2）转基因小鼠，称为K5.cox-2，100％的小鼠会发展为胰腺腺癌的胰腺炎。在肥胖小鼠中的胰腺病变的发展和IGF-1的因果关系。肥胖诱导的胰腺肿瘤的IGF-1水平降低，确定AIM 2的研究将确定肥胖饮食的增强，CR抑制，炎症（循环细胞因子水平和炎症细胞），IGF-1对IGF-1的贡献 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评估的浸润。 IGF-1R信号传导的MAPK途径将减少肥胖诱导的胰腺癌。确定肥胖对胰腺癌的影响的分子靶标：拟议的研究应提供有关肥胖症如何有助于胰腺癌的发展的新信息。

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