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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对这些过程有贡献，而获得性免疫对癌症发生的贡献则不太清楚。我们已经鉴定出一种人类结肠厌氧细菌，产肠毒素脆弱类杆菌(ETBF)，它能诱导多发性肠道肿瘤小鼠(MinApc)结肠肿瘤的快速和戏剧性增加。这个模型复制了人类结直肠癌的特征，我们的数据表明，在这个系统中，结肠癌的发生部分依赖于一个新的STAT3/Th17途径，从而定义了获得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在不同的细胞间隔中的激活以及Th17反应的结果成分与结肠上皮的相互作用，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的机制。我们的研究将开始确定特定炎症介质和基因变化之间的联系，这些基因变化对结肠癌的发生至关重要。这项工作与研究人类结直肠癌发病机制的研究设计有直接关系，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：结肠癌是导致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学机制尚不清楚。该项目将研究一种新发现的常见人类粪便细菌--产肠毒素脆弱类杆菌(ETBF)--触发小鼠结肠癌的免疫和遗传机制，为结肠癌的发展提供新的见解，并可能提供新的结肠癌治疗方法。