Mechanisms of cytokine driven tumor elicited inflammation in colorectal cancer

项目摘要 肿瘤微环境（TME），特别是肿瘤浸润性炎症细胞，是一个重要的组成部分， 肿瘤的发生。大多数实体瘤表现出一种自相矛盾的能力，即招募免疫细胞， 上调促进肿瘤进展的炎症介质。我们首先将这一过程定义为“肿瘤 引发炎症”（TEI），并表明在结直肠癌（CRC）中，TEI是在结肠癌早期诱导的。 肿瘤发生，特别是因为癌基因诱导的肿瘤特异性屏障恶化， 微生物产物易位通过一般抗炎药或特异性抗炎药抑制炎症 炎性信号传导节点（细胞因子、转录因子）的失活降低肿瘤发生率， 在动物模型中的生长，并降低癌症发展和相关的死亡在人类的风险。未解决 问题是TEI是如何被肿瘤诱导的，TEI维持的关键介质是什么， 肿瘤发生作用和TEI如何促进癌症以及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， IL-23调节对CRC生长至关重要的IL-17途径。然而，CRC-specific 微生物刺激，以及产生IL-23的髓样细胞的身份和表达IL-23 R的身份， IL-23反应性细胞未知。此外，虽然TEI很可能在治疗的后期阶段促进CRC 由于肿瘤的发展，不知道在结直肠癌开始时的“早期”TEI诱导是否对结直肠癌重要 结果基于初步数据，我们假设强粘附细菌刺激IL-23 IL-23在肿瘤骨髓细胞中的表达和IL-23激活T细胞和先天性巨噬细胞中促肿瘤发生IL-17的产生 淋巴样细胞（ILC）通过在CRC TME内起作用来促进CRC，并且该机制甚至在早期 《儿童权利公约》。为修订后的应用程序修改的拟议具体目标如下：（1）定义 控制CRC中TEI所需的肿瘤特异性微生物刺激。(2)定义肿瘤髓样细胞亚群 在CRC中IL-23产生和TEI诱导所需;和3）检查 IL-17 TEI介导CRC和CRC促进期间TEI的时间要求。 总的来说，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，以产生对特定微生物在诱导TEI促进CRC中的作用的基本见解。我们将 系统地测试TME内响应CRC特异性微生物信号的各种细胞区室， 产生IL-23并响应IL-23;以及TEI如何通过其对CRC TME内细胞的作用驱动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 微环境，并将确定新的预防/治疗突破的目标。这项工作将 为特定消除与风险相关的微生物种群和中和 CRC TME内的细胞因子途径作为限制CRC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.