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，会增强受影响器官的致癌作用。已知慢性先天免疫反应有助于这些过程，而适应性免疫对致癌作用的贡献尚不清楚。我们已经鉴定出一种人类结肠厌氧细菌，即产肠毒素脆弱拟杆菌 (ETBF)，它会诱导多发性肠道肿瘤小鼠 (MinApc) 的结肠肿瘤迅速而显着增加。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，我们试图进一步明确不同细胞区室中 Stat3 激活的机制以及 Th17 反应与结肠上皮串扰的结果成分，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对结肠癌发生至关重要的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。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。该项目将研究一种新发现的常见人类粪便细菌（称为产肠毒素脆弱拟杆菌（ETBF））引发小鼠结肠肿瘤的免疫和遗传机制，为结肠癌如何发展提供新见解，并为结肠癌治疗提供潜在的新方法。