Gut microbiota and inflammatory monocytes in colorectal cancer

结直肠癌中的肠道微生物群和炎症单核细胞

• 批准号: 8444653
• 负责人: Wendy S. Garrett
• 金额: $ 31.5万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-18 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444653
• 关键词: Adenocarcinoma; Age; Anti-Inflammatory Agents; Anti-inflammatory; Area; Automobile Driving; Bacteria; Biometry; Cancer Biology; Cancer Etiology; Cell Proliferation; Cells; Cellular biology; Cessation of life; Chronic; Colitis; Collaborations; Colon; Colon Carcinoma; Colorectal Cancer; Communities; Computational Biology; Computing Methodologies; Dana-Farber Cancer Institute; Data; Data Set; Dendritic Cells; Development; Digestive System Disorders; Disease; Dysplasia; Environment; Evolution; Germ-Free; Grant; Human; Immune; Immune response; Immunity; Immunology; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Institutes; Intestinal Cancer; Intestines; Light; Malignant Neoplasms; Microbe; Microbiology; Modeling; Molecular; Mucosal Immune Responses; Mucous Membrane; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Neoplasms; Patients; Penetrance; Population; Publishing; Research; Research Personnel; Risk Factors; Role; Shapes; Signal Pathway; Staging; Techniques; Technology; Therapeutic; Ulcerative Colitis; Universities; adaptive immunity; cancer cell; cancer therapy; carcinogenesis; functional genomics; genome sequencing; gut microbiota; high risk; human disease; insight; macrophage; medical schools; member; microbial community; microbial host; microorganism interaction; migration; monocyte; mouse model; neoplastic; prevent; public health relevance; response; stem; tool; transcriptomics; tumor; tumor microenvironment; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related death and the third most common cancer in the US. Inflammation is a key contributor to carcinogenesis, and there is an increased incidence of cancer in patients with chronic inflammatory diseases. Inflammation in the tumor microenvironment can enhance cancer cell proliferation, survival, and migration. A chronically inflamed colonic mucosa is pro- neoplastic; and ulcerative colitis (UC) is one of the highest risk factors for the development of CRC. Recent data suggest that immune responses to commensal gut bacteria may influence the development of CRC and colitis-associated colorectal cancer (caCRC). However, how the gut microbiota shapes mucosal immune responses leading to chronic inflammation and CRC is not well understood. Important questions include: (1) what are the features of the gut microbiota that elicit chronic inflammatory responses that drive caCRC and (2) how do mucosal innate immune subsets function in the evolving tumor microenvironment. This proposal builds on our recent studies of a spontaneous mouse model of UC and caCRC that is driven genetically by T-bet deficiency in the absence of adaptive immunity, and stems from our preliminary data on the microbial communities that instigate colitis. Our specific aims are to: 1) define the role of fecal microbial community members in initiating the innate immune driven inflammatory cascades that drive caCRC; 2) characterize monocyte populations and their recruitment, function, and response to the intestinal microbiota across the colitis r dysplasia r adenocarcinoma transition; and 3) perform a functional genomic analysis of fecal microbial communities across the colitis r dysplasia r adenocarcinoma transition. We employ cell biology, immunology, and microbiology techniques and sequencing technology as experimental tools, in conjunction, with computational methodology capable of integrating these diverse data sets. By analyzing the function of intestinal microbial communities and innate immune subsets in driving pro-neoplastic inflammation, this proposal will advance basic understanding of the contribution of host-microbial interactions to the evolution of a tumor microenvironment. Since we utilize a mouse model that is reminiscent of UC and recapitulates key features of human IBD-associated CRC, we anticipate that our data will be applicable for human disease and for the development of anti-inflammatory host and/or microbe directed therapeutics that will prevent the development and progression of cancer.

描述（由申请人提供）：结直肠癌（CRC）是美国癌症相关死亡的第二大原因，也是第三大常见癌症。炎症是致癌的关键因素，慢性炎症性疾病患者的癌症发病率增加。肿瘤微环境中的炎症可以增强癌细胞增殖、存活和迁移。慢性炎症的结肠粘膜是促肿瘤的;并且溃疡性结肠炎（UC）是发展CRC的最高风险因素之一。最近的数据表明，对肠道细菌的免疫反应可能会影响CRC和结肠炎相关结直肠癌（caCRC）的发展。然而，肠道微生物群如何塑造导致慢性炎症和CRC的粘膜免疫反应尚不清楚。重要问题包括：（1）引起慢性炎症反应的肠道微生物群的特征是什么，这些炎症反应驱动了caCRC;（2）粘膜先天免疫亚群如何在不断发展的肿瘤微环境中发挥作用。该提议建立在我们最近对UC和caCRC自发小鼠模型的研究基础上，该模型在缺乏适应性免疫的情况下由T-bet缺陷遗传驱动，并且源于我们关于引发结肠炎的微生物群落的初步数据。我们的具体目标是：1）确定粪便微生物群落成员在启动先天免疫驱动的炎症级联反应（驱动caCRC）中的作用; 2）表征单核细胞群体及其在结肠炎/发育异常/腺癌转变中的募集、功能和对肠道微生物群的反应; 3）对结肠炎/发育异常/腺癌转变中的粪便微生物群落进行功能基因组分析。我们采用细胞生物学，免疫学，微生物学技术和测序技术作为实验工具，结合计算方法，能够整合这些不同的数据集。通过分析肠道微生物群落和先天免疫亚群在驱动促肿瘤炎症中的功能，该提案将促进对宿主-微生物相互作用对肿瘤微环境演变的贡献的基本理解。由于我们利用了一种让人想起UC的小鼠模型，并概括了人类IBD相关CRC的关键特征，我们预计我们的数据将适用于人类疾病，并用于开发抗炎宿主和/或微生物导向的治疗方法，以预防癌症的发展和进展。