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: 8561433
• 负责人: STEPHEN J PANDOL
• 金额: $ 20.09万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8561433
• 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）在实体瘤中是独一无二的 围绕该肿瘤的癌细胞腺的脱粒反应。癌症的乳腺癌是 由肌纤维蛋白活化的胰腺星状细胞（PASC）产生的PASC时 产生大量细胞外基质（ECM）蛋白质，并通过提供PDAC的生长 癌细胞生长以及生长因子，血管生成因子和免疫的脚手架 调节器。有证据表明，癌细胞与活化的PASC之间的相互作用是 负责PDAC的生长，转移和化学抗性。我们建议各种系统性 在酒精滥用和高脂肪/高卡路里饮食（HFCD）中发生的因素刺激了 内源性静止的pascs促进其激活，肌纤维蛋白酶和胰腺癌促进状态。在 这种状态是星状细胞是胰腺癌发生的关键参与者。我们的假设指出酒精 滥用和HFCD促进脱木质，然后通过 酒精代谢物，Lepfin，胰岛素样生长因子1（IGF-1），脂多糖（LPS），肿瘤的影响 坏死因子A（TNF-A）和PASC上的低密度脂蛋白（OXLDL）氧化。这些调解人采取行动 PASC导致其激活，增殖，细胞外基质蛋白的产生和化学 对于促进胰腺癌至关重要的信号。这些效果在很大程度上介导 通过PASC的Pi 3kinase/Akt和MTOR信号传导系统。另外，这些系统因素与 癌症前体的Panin细胞调节其PI3Kinase/Akt和MTOR信号系统重新硫酸 分泌额外促进PASC的促促促促骨菌作用的因素。测试我们的 假设提出了以下具体目的：1）表征乙醇的作用（及其乙醇的作用） 代谢物），Lepfin，IGF-1，LPS，TNF-A，OXLDL在PASC pro-Carcinogenogation上； 2）确定 Pi 3kinase/ akt和MTOR信号系统在PASC促炎反应中的作用； 3）检查 乙醇进食对条件性kras®模型中PASC反应和PANLNS进展的影响 接受标准或高热量饮食； 4）在动物模型中确定体内的PASC响应 计划。 相关性（请参阅说明）： 我们的调查将证明酒精和饮食因素如何不利于胰腺癌发生 通过它们对代表癌症脱木质来源的胰腺星状细胞的影响。 由于新兴信息显示了星状细胞和脱木质在 胰腺癌发生，我们的结果将导致有关机制的新颖而可能的意外见解 促进胰腺癌导致重要的预防和治疗临床策略。