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：
8813782
负责人：
Venkatakrishna Rao Jala
金额：
$ 19.58万
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 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8813782
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 Human IL8 gene Immune Immune system Individual Infiltration Inflammation Inflammatory Interferon Type II 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 Transplantation Tumor Burden base carcinogenesis cell motility chemokine chemokine receptor colon tumorigenesis commensal microbes cytokine design gut microbiota gut microflora inhibitor/antagonist interleukin-23 macrophage mast cell monocyte mouse model neoplastic cell next generation sequencing novel therapeutic intervention novel therapeutics outcome forecast peripheral blood proxigermanium public health relevance 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（由申请人提供）：结直肠癌 (CRC) 与伴随白细胞浸润增加的炎症密切相关，CCR2 是一种七跨膜 G 蛋白偶联趋化因子受体，介导多种生物学功能，包括白细胞与其配体结合后的趋化性。 CCL2 (MCP1) 在外周血单核细胞/巨噬细胞以及活化的 T 细胞、B 细胞、未成熟细胞上表达。树突状细胞和肥大细胞中 CCL2 的表达升高与多种人类癌症的转移增加和预后不良密切相关。我们的初步数据表明，ApcMin/+（自发性肠癌小鼠模型）背景下的 CCR2-/- 小鼠产生的小肠和结肠肿瘤明显更少且更小，并且与相比，显示出显着的生存优势。此外，与 ApcMin/+ 小鼠相比，CCR2-/-ApcMin/+ 中的息肉显示肿瘤浸润 F4/80+ 细胞减少、炎症分子（例如 IL-1β、SOCS1）减少、细胞凋亡和 CD8 水平增加。提示，CCR2-/-ApcMin/+ 中的炎症细胞因子 IL-23 和 IL-17 显着减少。我们的肠道微生物群分析显示，促进肿瘤的拟杆菌属。与 ApcMin/+ 小鼠相比，CCR2-/-ApcMin/+ 小鼠中的 CCR2/CCL2 介导的肿瘤相关巨噬细胞 (TAM) 和 Th17 细胞的募集显着减少，从而调节肿瘤中的炎症和微生物群。促进肠道肿瘤的微环境和阻断 CCR2-CCL2 轴将减少肿瘤负担，为了检验这一假设，我们在 AIM 1 中提出了具体目标。在肠道肿瘤发生过程中招募和激活产生 IL-23（TAM、DC）和 IL-17（Th17、ɣδ T 细胞）的细胞。在 AIM 2 中，我们将确定肠道微生物群对 CCR2 依赖的 IL-产生的影响。 23 和 IL-17 促进肠道肿瘤发生。目前的提案还将检查现有 CCR2 抑制剂在结肠癌进展中的功效，以转化我们在临床前模型中的基本观察结果。确定癌症背景下免疫系统-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癌发生的基本理解以及开发新治疗策略的潜力产生重大影响。