CCR2 mediated inflammation and gut microbiota in promoting intestinal cancer

CCR2 介导的炎症和肠道微生物群促进肠癌

基本信息

批准号：
8990832
负责人：
Venkatakrishna Rao Jala
金额：
$ 16.31万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8990832
关键词：
Adoptive Transfer Animal Model Antibiotics ApcMin/+ mice Apoptosis B-Lymphocytes Bacteria Bacteroides Bacteroides fragilis Binding Biological Process CCL2 gene CD4 Positive T Lymphocytes CD8B1 gene Cancer Etiology Cells Cessation of life Chemotaxis Colitis Colon Carcinoma Colonic Neoplasms Colorectal Cancer Complex Coupled Data Dendritic Cells Development Epithelial Epithelial Cells Equilibrium Event Family Figs - dietary GTP-Binding Proteins Genes Genetic Granzyme Health Human IL8 gene Immune Immune system Individual Infiltration Inflammation Inflammatory Interferon Type II Interleukin-1 beta Interleukin-17 Interleukin-6 Intestinal Cancer Intestinal Neoplasms Intestines Lactobacillus acidophilus Lamina Propria Leukocyte Chemotaxis Leukocytes Ligands Link Lymphoid Cell Malignant Neoplasms Mediating Methods Modeling Molecular Monocyte Chemoattractant Proteins Mus Mutation Myeloid Cells NF-kappa B Neoplasm Metastasis Pathway interactions Play Polyps Pre-Clinical Model Probiotics Process Production Recruitment Activity Role STAT3 gene Signal Transduction Spleen T-Cell Proliferation T-Lymphocyte TNF gene Testing Translating Tumor Burden base carcinogenesis cell motility chemokine chemokine receptor colon tumorigenesis commensal microbes cytokine design fecal transplantation gut microbiota inhibitor/antagonist interleukin-23 macrophage microbiota monocyte mouse model neoplastic cell next generation sequencing novel therapeutic intervention novel therapeutics outcome forecast peripheral blood research study response seven-transmembrane G-protein-coupled receptor small molecule transcription factor tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is strongly associated with inflammation accompanied by increased infiltration of leukocytes. CCR2, a seven transmembrane G-protein coupled chemokine receptor, mediates several biological functions including chemotaxis of leukocytes upon binding to its ligand, CCL2 (MCP1). CCR2 is expressed on peripheral blood monocytes/macrophages as well as on activated T-cells, B-cells, immature dendritic cells and mast cells. Elevated expression of CCL2 in tumor cells is very well correlated with increased metastasis and poor prognosis in several types of human cancers. Recently, it was shown in animal models that CCL2-CCR2 axis play an important role in promotion of colon tumorigenesis. Our preliminary data showed that CCR2-/- mice in the ApcMin/+ (a spontaneous intestinal cancer mouse model) background developed significantly fewer and smaller size small intestinal and colon tumors and showed substantial survival advantage compared to ApcMin/+ mice. Further, polyps in CCR2-/-ApcMin/+ displayed decreased tumor infiltrating F4/80+ cells, decreased inflammatory molecules (e.g., IL-1β, SOCS1), increased apoptosis and CD8 levels compared to ApcMin/+ mice. Interestingly, inflammatory cytokines IL-23 and IL-17 were significantly reduced in CCR2-/-ApcMin/+. Our gut microbiota analysis revealed that tumor promoting Bacteroides genus are significantly reduced in CCR2-/-ApcMin/+ mice compared to ApcMin/+ mice. Based on these preliminary data we hypothesize that CCR2/CCL2 mediated recruitment of tumor associated macrophages (TAMs) and Th17 cells modulate inflammation and microbiota in the tumor microenvironment to promote intestinal tumors and blocking CCR2-CCL2 axis would reduce the tumor burden. To test this hypothesis we propose two specific aims. In AIM 1 we will determine the requirement of CCR2 for recruitment and activation of IL-23 (TAMs, DCs) and IL-17 (Th17, ɣδ T-cells) producing cells during intestinal tumorigenesis. In AIM 2, we will determine the influence of gut microflora on CCR2 dependent production of IL-23 and IL-17 to promote intestinal tumorigenesis. The current proposal will also examine the efficacy of existing CCR2 inhibitors in colon cancer progression to translate our basic observation in pre-clinical models. Determining the molecular, cellular mechanisms and complex inter-relationship between immune system-microbiota in the context of cancer will have a strong impact on our basic understanding of intestinal carcinogenesis as well as potential for developing novel therapeutic strategies.

描述（由适用提供）：结直肠癌（CRC）与白细胞浸润增加而达到的炎症密切相关。 CCR2是一种七个跨膜G蛋白偶联趋化因子受体，介导了几种生物学功能，包括白细胞与其配体CCL2（MCP1）结合后白细胞的趋化性。 CCR2在外周血单核细胞/巨噬细胞以及活化的T细胞，B细胞，未成熟的树突状细胞和肥大细胞上表达。 CCL2在肿瘤细胞中的表达升高与几种类型的人类癌症的转移和预后不良非常相关。最近，在动物模型中表明，CCL2-CCR2轴在促进结肠肿瘤发生中起着重要作用。 Our preliminary data shown that CCR2-/- mice in the ApcMin/+ (a sponsor-intestinal cancer mouse model) background developed More polyps in CCR2-/-ApcMin/+ displayed decreased tumor infiltrating F4/80+ cells, decreased inflammatory molecules (e.g., IL-1β, SOCS1), increased apoptosis and CD8 levels compared to ApcMin/+ mice.有趣的是，在CCR2 - / - APCMIN/+中，炎性细胞因子IL-23和IL-17的降低明显降低。我们的肠道菌群分析表明，与APCMIN/+小鼠相比，CCR2 - / - APCMIN/+小鼠中促进菌烯属属的属性显着降低。根据这些初步数据，我们假设CCR2/CCL2介导的肿瘤相关巨噬细胞（TAMS）和TH17细胞在肿瘤微环境中调节注射和菌群，以促进肠道肿瘤，以促进CCR2-CCL2轴可减少肿瘤燃烧。为了检验这一假设，我们提出了两个具体目标。在AIM 1中，我们将确定CCR2对在肠道肿瘤发生期间产生细胞的IL-23（TAM，DC）和IL-17（Th17，ɣδT细胞）的募集和激活的需求。在AIM 2中，我们将确定肠道菌群对IL-23和IL-17的CCR2依赖性产生的影响，以促进肠道肿瘤发生。提案还将检查现有的CCR2抑制剂在结肠癌进展中的有效性，以在临床前模型中翻译我们的基本观察结果。在癌症的背景下，确定免疫系统 - 微生物群之间的分子，细胞机制和复杂的相互关系将对我们对肠道致癌作用的基本理解以及发展新型治疗策略的潜力。