Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis

TH17炎症诱导的结肠癌发生机制

基本信息

批准号：
8105255
负责人：
DREW M. PARDOLL
金额：
$ 33.01万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-06 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8105255
关键词：
Ablation Acute Address Affect Alleles Anaerobic Bacteria Bacteria Bacteroides fragilis Bone Marrow CD4 Positive T Lymphocytes Cancer Etiology Cells Cessation of life Characteristics Chimera organism Chromosomal Instability Chronic Colitis Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Data Dependence Development Epigenetic Process Epithelial Epithelial Cells Epithelium Equilibrium Etiology Feces Genes Genetic Growth Hematopoietic Human Hyperplasia IkappaB kinase Immune Immune response Immunologics Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Infrequent Neoplasm Interleukin-17 Interleukin-6 Intestinal Neoplasms Intracolonic Knock-out Knockout Mice Link Loss of Heterozygosity Lymphoid Malignant Neoplasms Malignant neoplasm of liver Measurement Mediating Metalloproteases Microsatellite Instability Modeling Mus Mutation Myelogenous Natural Immunity Nitrogen Oral Administration Organ Oxygen Pathogenesis Pathway interactions Premalignant Process Production Property Public Health Research Design Role Signal Transduction Source System T-Lymphocyte Toll-like receptors Toxin United States Woman Work adaptive immunity base cancer therapy carcinogenesis cellular targeting colon carcinogenesis cytokine insight interleukin-22 interleukin-23 laser capture microdissection malignant stomach neoplasm men microbial novel novel strategies public health relevance receptor response tumor tumor progression tumorigenesis

项目摘要

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.

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，增强了受影响器官的致癌作用。已知慢性先天免疫反应会导致这些过程，而适应性免疫对癌变的贡献则不太清楚。我们已经鉴定出人类结肠厌氧菌，肠毒性杀菌剂fragilis（ETBF），该细菌（ETBF）诱导了多个肠道肿瘤小鼠（MinAPC）的结肠肿瘤的快速而急剧增加。该模型复制了人类结肠癌的特征，我们的数据表明，该系统中的结肠肿瘤发生在某种程度上取决于新型的STAT3/TH17途径，从而确定了在结肠癌发病机理中适应性免疫的独特作用。在此，我们寻求进一步定义了在不同的细胞室中激活STAT3的机制，以及Th17反应串扰与结肠上皮的串扰的结果成分，从而诱导遗传和/或表观遗传上皮细胞变化，从而导致结肠肿瘤发生。我们的研究将开始确定特定炎症介质与结肠癌发生至关重要的遗传变化之间的联系。这项工作与研究研究人结直肠癌的发病机理的设计具有直接相关性，并可能对新型结直肠癌治疗的方法有影响。大肠癌是主要的公共卫生问题，是美国男性和男性癌症死亡的第二大原因。公共卫生相关性：结肠癌是男女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。该项目将研究一种新认可的称为肠毒素菌菌素fragilis（ETBF）触发小鼠的结肠肿瘤的免疫和遗传机制，通过该机制，可以提供新的见解，从而提供有关结肠癌如何发展为结肠癌治疗的潜在新方法的新见解。