Alchol Abuse and Metabolic Syndrome Promote Desmoplasia of Pancreatic Cancer

酒精滥用和代谢综合征促进胰腺癌结缔组织增生

• 批准号: 8401917
• 负责人: STEPHEN J PANDOL
• 金额: $ 20.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401917
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adenocarcinoma; Alcohol abuse; Alcohols; Angiogenic Factor; Animal Model; Cells; Chemicals; Chronic; Clinical; Development; Diet; Dietary Factors; Ductal; Ethanol; Extracellular Matrix; Extracellular Matrix Proteins; Fatty acid glycerol esters; Gland; Growth; Growth Factor; Immune; Instruction; Insulin-Like Growth Factor I; Lead; Leptin; Lipopolysaccharides; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Mediator of activation protein; Metabolic syndrome; Modeling; Neoplasm Metastasis; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Participant; Principal Investigator; Production; Reaction; Role; SHH gene; Signal Transduction; Solid Neoplasm; Source; System; Testing; The Sun; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; alcohol effect; alcohol response; cancer cell; carcinogenesis; feeding; human FRAP1 protein; in vivo; insight; novel; oxidized low density lipoprotein; programs; response; scaffold; stellate cell; tumor

Pancreatic ductal adenocarcinoma (PDAC) is unique among solid tumors because of the extremely dense desmoplasfic reaction that surrounds the cancer cell glands of this tumor. The cancer desmoplasia is produced by the myofibroblasfic activated pancreatic stellate cell (PaSC) The PaSCs when acfivated produce large amounts of extracellular matrix (ECM) proteins and modulate the growth of PDAC by providing a scaffold for the cancer cells to grow as well as growth factors, angiogenesis factors and immune modulators. Evidence is mounting that interplay between the cancer cells and activated PaSCs are responsible for the growth, metastasis and chemoresistance of PDAC. We propose that various systemic factors occurring in alcohol abuse and high fat/high calorie diet (HFCD) stimulate conversion of the endogenous quiescent PaSCs to their activated, myofibroblasfic and pancreafic cancer promoting state. In this state the stellate cell is a key participant in pancreafic carcinogenesis. Our hypothesis states that alcohol abuse and HFCD promote desmoplasia and, in turn, promote the development of pancreafic cancer through the effects of alcohol metabolites, lepfin, insulin-like growth factor-1 (IGF-1), lipopolysaccharide (LPS), tumor necrosis factor-a (TNF-a) and oxidized low density lipoprotein (oxLDL) on PaSCs. These mediators act on PaSCs resulting in their activation, proliferation, production of extracellular matrix proteins and chemical signals that are essential for promotion of pancreatic cancer. These effects are mediated in large part through the PI 3kinase/Akt and mTOR signaling systems of PaSCs. Also, these systemic factors interact with cancer precursors PanIN cells regulafing their PI3kinase/Akt and mTOR signaling systems resulfing in the secretion of factors that additionally promote the procarcinogenic effects of the PaSCs. To test our hypothesis the following Specific Aims are proposed: 1) to characterize the effects of ethanol (and its metabolites), lepfin, IGF-1, LPS, TNF-a, oxLDL on PaSC pro-carcinogenic responses; 2) to determine the role of the PI 3kinase/ Akt and mTOR signaling system in PaSC procarcinogenic responses; 3) to examine the effects of ethanol feeding on PaSC responses and PanlNs progression in the conditional Kras¿^^¿ model subjected to standard or high caloric diets; and 4) to determine PaSC responses in vivo in the animal models ofthe program. RELEVANCE (See instructions): Our invesfigations will demonstrate how alcohol and dietary factors infiuence pancreatic carcinogenesis through their effects on the pancreatic stellate cell which represents the source of cancer desmoplasia. Because of emerging information showing the important role of the stellate cell and desmoplasia in pancreatic carcinogenesis, our results will lead to novel and likely unexpected insights about the mechanism of promotion of pancreatic cancer leading to important preventative and therapeutic clinical strategies.

胰腺导管腺癌（PDAC）是实体瘤中的独特之处，因为它具有极高的密度， 肿瘤的癌细胞腺体周围的结缔组织增生反应。癌性结缔组织增生是 由成肌纤维细胞活化的胰腺星状细胞（PaSC）产生。 产生大量的细胞外基质（ECM）蛋白，并通过提供 癌细胞生长的支架以及生长因子、血管生成因子和免疫调节因子， 调制器。越来越多的证据表明，癌细胞和激活的PaSC之间的相互作用是 负责PDAC的生长、转移和化学抗性。我们建议，各种系统 酒精滥用和高脂肪/高热量饮食（HFCD）中发生的因素刺激了 在一些实施方案中，细胞因子可将内源性静止PaSC转化为其活化的、肌纤维母细胞和胰腺癌促进状态。在 在这种状态下，星状细胞是胰腺癌发生的关键参与者。我们的假设是酒精 滥用和HFCD促进结缔组织增生，反过来又促进胰腺癌的发展， 酒精代谢产物、瘦素、胰岛素样生长因子-1（IGF-1）、脂多糖（LPS）、肿瘤 坏死因子-α（TNF-α）和氧化低密度脂蛋白（oxLDL）。这些调解人采取行动， PaSC导致其活化、增殖、产生细胞外基质蛋白和化学物质 这些信号对促进胰腺癌的发生至关重要。这些影响在很大程度上是由 通过PaSCs的PI 3激酶/Akt和mTOR信号系统。此外，这些系统性因素与 癌前体PanIN细胞调节其PI 3激酶/Akt和mTOR信号系统，导致 分泌额外促进PaSC的原致癌作用的因子。来测试我们 假设提出了以下具体目的：1）表征乙醇（及其 代谢物）、瘦素、IGF-1、LPS、TNF-α、oxLDL对PaSC促癌反应的影响; 2）确定 PI 3激酶/ Akt和mTOR信号系统在PaSC致癌反应中的作用; 3）检查 在条件Kras模型中，乙醇喂养对PaSC反应和PanLN进展的影响 进行标准或高热量饮食;和4）在动物模型中测定体内PaSC应答 的程序。 相关性（参见说明）： 我们的研究将证明酒精和饮食因素如何影响胰腺癌的发生 通过它们对胰腺星状细胞的作用，而星状细胞是癌症结缔组织增生的来源。 由于新出现的信息显示星状细胞和结缔组织增生在 胰腺癌的发生，我们的研究结果将导致新的和可能意想不到的见解的机制 促进胰腺癌导致重要的预防和治疗临床策略。