Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis

描述（由申请人提供）：慢性炎症，特别是感染相关的炎症过程，可增强受影响器官的致癌作用。慢性先天免疫反应是已知的，有助于这些过程，而适应性免疫致癌的贡献不太清楚。我们已经确定了一种人结肠厌氧菌，肠促炎脆弱拟杆菌（ETBF），诱导结肠肿瘤在多发性肠肿瘤小鼠（MinApc）的快速和显着的增加。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新的Stat 3/Th 17通路，从而定义了适应性免疫在结肠癌发病机制中的独特作用。在此，我们寻求进一步定义的机制，其中Stat 3激活在不同的细胞隔室和由此产生的组件的Th 17响应串扰与结肠上皮，诱导遗传和/或表观遗传上皮细胞的变化，导致结肠肿瘤的发生。我们的研究将开始，以确定特定的炎症介质和结肠癌发生的关键基因变化之间的联系。这项工作与研究人类结直肠癌发病机制的研究设计直接相关，并可能对结直肠癌治疗的新方法产生影响。结直肠癌是一个主要的公共卫生问题，是美国女性和男性癌症死亡的第二大原因。 公共卫生相关性：结肠癌是女性和男性癌症死亡的第二大原因。导致结肠癌的微生物和免疫机制尚不清楚。该项目将研究免疫和遗传机制，通过这种机制，一种新发现的常见人类粪便细菌，称为肠促炎性脆弱拟杆菌（ETBF），在小鼠中引发结肠肿瘤，为结肠癌如何发展提供新的见解，并为结肠癌治疗提供潜在的新方法。

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. PUBLIC HEALTH RELEVANCE: Colon cancer is the second leading cause of cancer death for women and men. The microbial and immunologic mechanisms contributing to colon cancer are unknown. This project will study the immune and genetic mechanisms by which a newly recognized common human stool bacterium called enterotoxigenic Bacteroides fragilis (ETBF) triggers colon tumors in mice, providing new insights into how colon cancer developes and potentially new approaches to colon cancer therapy.