Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis

描述（由申请人提供）：慢性炎症，特别是与感染相关的炎症过程，增强受影响器官的癌变。已知慢性先天免疫反应有助于这些过程，而适应性免疫对癌变的贡献则不太清楚。我们已经鉴定出一种人类结肠厌氧细菌，肠产毒素脆弱拟杆菌（ETBF），可诱导多发性肠瘤小鼠（MinApc）结肠肿瘤的快速和急剧增加。该模型复制了人类结直肠癌的特征，我们的数据表明，该系统中的结肠肿瘤发生部分依赖于一种新的Stat3/Th17途径，从而确定了适应性免疫在结肠癌发病机制中的独特作用。在此，我们试图进一步确定Stat3在不同细胞区室中的激活机制，以及Th17应答与结肠上皮的串扰，诱导导致结肠肿瘤发生的遗传和/或表观遗传上皮细胞变化。我们的研究将开始确定特定炎症介质和对结肠癌发生至关重要的遗传变化之间的联系。这项工作与研究人类结直肠癌发病机制的设计直接相关，并可能对结直肠癌治疗的新方法产生影响。结直肠癌是一个重大的公共卫生问题，是美国女性和男性癌症死亡的第二大原因。

DESCRIPTION (provided by applicant): Chronic inflammation and, specifically, infection-associated inflammatory processes, enhance carcinogenesis in the affected organs. Chronic innate immune responses are known to contribute to these processes whereas the contributions of adaptive immunity to carcinogenesis are less clear. We have identified a human colon anaerobic bacterium, enterotoxigenic Bacteroides fragilis (ETBF), that induces a rapid and dramatic increase in colon tumors in multiple intestinal neoplasia mice (MinApc). This model replicates features of human colorectal cancer and our data demonstrate that colon tumorigenesis in this system is dependent, in part, on a novel Stat3/Th17 pathway, thereby defining a distinct role for adaptive immunity in colon cancer pathogenesis. Herein we seek to further define the mechanisms by which Stat3 activation in distinct cellular compartments and the resultant components of the Th17 response crosstalk with the colonic epithelium, inducing genetic and/or epigenetic epithelial cell changes that result in colon tumorigenesis. Our studies will begin to identify links between specific inflammatory mediators and the genetic changes critical to colon carcinogenesis. This work has direct relevance to the design of studies to investigate the pathogenesis of human colorectal cancer and may have implications for novel approaches to colorectal cancer therapy. Colorectal cancer is a major public health problem being the second leading cause of cancer death in the United States in women and men.