Mechanisms of cytokine driven tumor elicited inflammation in colorectal cancer

项目总结 肿瘤微环境(TME)，尤其是肿瘤浸润性炎性细胞是肿瘤的重要组成部分 关于肿瘤发生的研究。大多数实体瘤表现出一种矛盾的能力，即招募免疫细胞和 上调有助于肿瘤进展的炎性介质。我们首先把这个过程定义为“肿瘤” 在结直肠癌(CRC)中，TEI是在早期诱发的。 肿瘤的发生，特别是由于癌基因诱导的，肿瘤特异性屏障和 微生物产物的转移。用普通抗炎药或特效抗炎药抑制炎症 炎性信号节点(细胞因子、转录因子)失活可降低肿瘤发病率和 在动物模型中生长，并降低人类患癌症和相关死亡的风险。未解决 问题是肿瘤是如何诱发TEI的，TEI维持的关键介质是什么，它的促进作用是什么。 致癌作用和TEI如何促进癌症？TEI作用的时间要求是什么？ 在这里，我们将揭示CRC中的TEI机制。从我们以前的工作和初步数据来看， IL-23调控IL-17途径，而IL-17途径对结直肠癌的生长至关重要。但是，CRC的身份特定 微生物刺激，以及产生IL-23的髓系细胞的身份和IL-23R表达的身份， IL-23反应细胞尚不清楚。此外，虽然TEI很可能在以下阶段促进《儿童权利公约》 肿瘤的发展，尚不清楚在结直肠癌初期的早期TEI诱导对结直肠癌是否重要 外延生长。根据初步数据，我们假设强粘附性细菌刺激IL-23 肿瘤髓系细胞和IL-23的表达激活T细胞和天然T细胞产生促肿瘤IL-17 淋巴样细胞(ILC)通过在CRC TME内起作用来促进CRC，该机制甚至在早期就开始运作。 CRC。为经修订的申请而修改的拟议具体目标如下：(1)界定 控制结直肠癌TEI所需的肿瘤特异性微生物刺激。(2)确定肿瘤髓系细胞亚群 IL-23的产生和TEI在结直肠癌中的诱导所需的；以及3)研究 IL-17 TEI调节CRC和CRC推广期间对TEI的时间需求。 总体而言，这些研究代表了一种综合免疫学、遗传学和癌症的方法。 生物学提供对特定微生物在诱导TEI促进结直肠癌中的作用的基本见解。我们会 有条不紊地测试TME内响应CRC特定微生物信号的各种细胞室， 产生IL-23和响应IL-23；以及TEI如何通过对CRC TME内的细胞的作用来驱动CRC。 这将是了解炎症细胞和癌细胞如何在肿瘤内交流的关键。 并将确定新的预防/治疗突破的目标。这项工作将 为具体消除与风险相关的微生物种群和中和 细胞因子途径在结直肠癌TME中作为限制结直肠癌进展的手段。

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.