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: 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
• 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

 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、未成熟树突状细胞和肥大细胞上表达。肿瘤细胞中 CCL2 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。最近，动物模型显示CCL2-CCR2轴在促进结肠肿瘤发生中发挥重要作用。我们的初步数据显示，与 ApcMin/+ 小鼠相比，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。有趣的是，CCR2-/-ApcMin/+ 中炎症细胞因子 IL-23 和 IL-17 显着减少。我们的肠道微生物群分析显示，与 ApcMin/+ 小鼠相比，CCR2-/-ApcMin/+ 小鼠中促进肿瘤的拟杆菌属显着减少。 基于这些初步数据，我们假设 CCR2/CCL2 介导肿瘤相关巨噬细胞 (TAM) 和 Th17 细胞的募集，调节肿瘤微环境中的炎症和微生物群，从而促进肠道肿瘤，而阻断 CCR2-CCL2 轴将减轻肿瘤负荷。为了检验这一假设，我们提出了两个具体目标。在 AIM 1 中，我们将确定肠道肿瘤发生过程中 CCR2 对产生 IL-23（TAM、DC）和 IL-17（Th17、ɣδ T 细胞）的细胞的招募和激活的需求。在 AIM 2 中，我们将确定肠道菌群对 CCR2 依赖性 IL-23 和 IL-17 产生的影响，从而促进肠道肿瘤发生。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。

项目成果

Colonic crypts are natural gatekeepers of microbial metabolites to protect stem cells.

结肠隐窝是微生物代谢物的天然看门人，可以保护干细胞。

• DOI: 10.21037/tcr.2016.08.24
• 发表时间: 2016
• 期刊: Translational cancer research
• 影响因子: 0.9
• 作者: Vemula,PraveenKumar;Jala,VenkatakrishnaRao
• 通讯作者: Jala,VenkatakrishnaRao