Mechanisms of cytokine driven tumor elicited inflammation in colorectal cancer

细胞因子驱动的肿瘤引发结直肠癌炎症的机制

• 批准号: 10245810
• 负责人: Sergei I. Grivennikov
• 金额: $ 46.11万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245810
• 关键词: 16S ribosomal RNA sequencing; Ablation; Adhesives; Animal Model; Anti-Inflammatory Agents; Antibiotics; Antibodies; Aspirin; Bacteria; Biological Markers; CDX2 gene; Cancer Biology; Cancer Etiology; Cell Communication; Cell Compartmentation; Cells; Cessation of life; Chronic; Colorectal Cancer; Common Neoplasm; Data; Deterioration; Development; Epithelial; Epithelium; First Name; Genetic; Germ-Free; Growth; Human; ITGAM gene; Immune; Immunology; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Interleukin-17; Knockout Mice; Lymphoid Cell; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Methods; Microbe; Mus; Myelogenous; Myeloid Cells; Myeloproliferative disease; Nature; Normal tissue morphology; Oncogenes; Pathway interactions; Pharmaceutical Preparations; Population; Preventive; Preventive measure; Process; Production; Public Health; Receptor Cell; Risk; Role; Scheme; Shapes; Signal Transduction; Site; Solid; Solid Neoplasm; Stimulus; Surface; T-Lymphocyte; Taxonomy; Testing; Therapeutic; Time; Tumor Tissue; Tumor stage; Work; base; cancer cell; cancer risk; cell type; colon cancer patients; colorectal cancer progression; cytokine; insight; interleukin-23; macrophage; microbial; monocyte; mortality; mouse model; neutrophil; novel; novel therapeutics; outcome forecast; receptor; recruit; transcription factor; tumor; tumor initiation; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis; tumorigenic

PROJECT SUMMARY Tumor microenvironment (TME), particularly tumor-infiltrating inflammatory cells, is an essential component of tumorigenesis. Most of the solid tumors demonstrate a paradoxical ability to recruit immune cells and to upregulate inflammatory mediators which assist tumor progression. We first defined this process as “Tumor elicited inflammation” (TEI) and suggested that in colorectal cancer (CRC), TEI is induced early during the tumorigenesis, particularly because of the oncogene-induced, tumor specific deterioration of barrier and microbial product translocation. Inhibition of inflammation by general anti-inflammatory drugs or by specific inactivation of inflammatory signaling nodes (cytokines, transcription factors) decreases tumor incidence and growth in animal models and reduces the risk of cancer development and related death in humans. Unresolved questions are how TEI is induced by tumors, what are the critical mediators of TEI maintenance and its pro- tumorigenic action and how TEI acts to promote cancer and what are the time requirements for TEI action? Here we will uncover TEI mechanisms in CRC. From our previous work and preliminary data it is known that IL-23 regulates the IL-17 pathway that is essential for CRC growth. However, the identity of CRC-specific microbial stimuli, as well as the identity of myeloid cells producing IL-23 and the identity of IL-23R expressing, IL-23-responsive cells is not known. Furthermore, while it is likely that TEI promotes CRC during later stages of tumor development, it is not known whether “early” TEI induction during CRC inception is important for CRC outgrowth. Based on preliminary data we hypothesize that strongly adhesive bacteria stimulate IL-23 expression in tumor myeloid cells and IL-23 activates pro-tumorigenic IL-17 production from T cells and innate lymphoid cells (ILC) to promote CRC by acting within CRC TME, and that mechanisms operate even in early CRC. Proposed Specific Aims which are modified for the revised application are the following: (1) Define the tumor-specific microbial stimuli required to control TEI in CRC. (2) Define subsets of tumor myeloid cells required for IL-23 production and TEI induction in CRC; and 3) Examine microenvironmental mechanisms of IL-17 TEI mediated CRC and temporal requirements for TEI during CRC promotion. Overall, these studies represent a comprehensive approach integrating immunology, genetics and cancer biology to yield basic insights into the role of specific microbes in inducing TEI to promote CRC. We will methodically test various cell compartments within the TME responding to CRC-specific microbial signals, producing IL-23 and responding to IL-23; and how TEI drives CRC via its action on cells within the CRC TME. This will be a key to understand how inflammatory and cancer cells communicate within the Tumor Microenvironment and will identify targets for novel preventive/therapeutic breakthroughs. This work will establish a rationale for the specific elimination of risk-associated populations of microbes and neutralization of cytokine pathways within the CRC TME as a means of limiting CRC progression.

项目摘要 肿瘤微环境（TME），尤其是肿瘤浸润细胞，是必不可少的成分 肿瘤发生。大多数实体瘤表现出招募免疫细胞的矛盾能力，并 上调有助于肿瘤进展的炎症介质。我们首先将此过程定义为“肿瘤 引起炎症”（TEI），并建议在结直肠癌（CRC）中，TEI在早期诱导 肿瘤发生，特别是因为癌基因引起的肿瘤特异性屏障和肿瘤特异性恶化和 微生物产品易位。普通抗炎药抑制炎症或特定 炎症信号淋巴结（细胞因子，转录因子）的失活会下降肿瘤的发生率和 动物模型的增长并降低了人类癌症发展和相关死亡的风险。未解决 问题是TEI诱导肿瘤的诱导方式，TEI维护的关键介体及其促进者是什么 肿瘤性作用以及TEI如何作用促进癌症以及TEI作用的时间要求是什么？ 在这里，我们将在CRC中发现TEI机制。从我们以前的工作和初步数据来看 IL-23调节对CRC生长至关重要的IL-17途径。但是，CRC特异性的身份 微生物刺激以及产生IL-23的髓样细胞的身份和IL-23R表达的身份， IL-23反应性细胞尚不清楚。此外，虽然TEI可能会在后期的阶段提升CRC 肿瘤发展，尚不清楚CRC成立期间“早期” TEI诱导对CRC是否重要 出生。根据初步数据，我们假设强烈粘合细菌刺激IL-23 肿瘤髓样细胞和IL-23中的表达激活了T细胞和先天的促肿瘤IL-17产生 淋巴样细胞（ILC）通过在CRC TME内作用来促进CRC，并且该机制即使在早期也起作用 CRC。建议为修订应用程序修改的特定目标如下：（1）定义 控制CRC中的TEI所需的肿瘤特异性微生物刺激。 （2）定义肿瘤髓样细胞的子集 CRC中IL-23生产和TEI诱导所需的必需； 3）检查的微环境机制 IL-17 TEI介导的CRC和CRC促销期间TEI的临时要求。 总体而言，这些研究代表了整合免疫学，遗传学和癌症的全面方法 生物学对特定微生物在诱导的TEI中的作用产生基本见解以促进CRC。我们将 有条不紊地测试TME内的各种细胞室，以响应CRC特异性微生物信号， 产生IL-23并响应IL-23；以及TEI如何通过对CRC TME内部细胞的作用来驱动CRC。 这将是了解炎症性和癌细胞如何在肿瘤内进行通信的关键 微环境将确定新型预防/治疗性突破的目标。这项工作将 建立一个理由，用于特异性消除微生物的风险相关人群和神经仿真 CRC TME内的细胞因子途径是限制CRC进展的一种手段。