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

• 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
• 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

 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.