Alchol Abuse and Metabolic Syndrome Promote Desmoplasia of Pancreatic Cancer

胰腺导管腺癌(PDAC)是实体瘤中独一无二的，因为它的密度极高。 围绕肿瘤癌细胞腺体的促结缔组织反应。癌结缔组织增生症是 由肌成纤维细胞激活的胰星状细胞(PASC)激活时产生 产生大量细胞外基质(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 调制器。越来越多的证据表明，癌细胞和激活的PaSCs之间的相互作用是 与PDAC的生长、转移和化疗耐药有关。我们建议各种系统性的 酒精滥用和高脂肪/高卡路里饮食(HFCD)中的因素刺激 内源性静止的PaSCs对其激活、肌纤维母细胞和胰腺癌促进状态的影响。在……里面 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促进促结缔组织发育，进而通过以下途径促进胰腺癌的发展 酒精代谢产物瘦素、胰岛素样生长因子-1、脂多糖对肿瘤的影响 PASCs上的肿瘤坏死因子-a(TNF-a)和氧化型低密度脂蛋白(OxLDL)。这些调解人采取行动 导致其激活、增殖、产生细胞外基质蛋白和化学物质的PaSCs 对促进胰腺癌至关重要的信号。这些影响在很大程度上是通过中介实现的。 通过PaSCs的PI3K/Akt和mTOR信号系统。此外，这些系统性因素与 癌前体细胞中的PAN调节其PI3K/Akt和mTOR信号系统，从而导致 分泌额外促进PaSCs致癌作用的因子。测试我们的 假设提出了以下具体目标：1)表征乙醇的影响(及其 代谢产物)、瘦素、IGF-1、内毒素、肿瘤坏死因子-α、氧化低密度脂蛋白对PASC促癌反应的影响；2)测定 PI-3K/Akt和mTOR信号系统在PASC癌前反应中的作用；3)检测 条件Kras模型中乙醇喂养对PASC反应和Panlns级数的影响 接受标准或高热量饮食；4)在动物模型中测定PASC的活体反应 程序的一部分。 相关性(请参阅说明)： 我们的研究将展示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影响，而星状细胞是癌症结缔组织增生的来源。 由于新出现的信息表明星状细胞和促结缔组织发育在 胰腺癌的发生，我们的结果将导致对机制的新的和可能意想不到的洞察 促进胰腺癌的发展导致重要的预防和治疗临床策略。

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.