Role of Bacteria in Colitis-Associated Colon Cancer

描述（由申请人提供）：结直肠癌（CRC）是美国男性和女性中第三大最常见的癌症形式，也是癌症相关死亡的第二大原因。慢性肠道炎症已被确定为结直肠癌发展的重要危险因素，因此患有炎症性肠病（IBD）的个体处于高风险。微生物群在结直肠癌发展中的作用尚未明确定义。迄今为止，研究主要集中在先天传感器和相关宿主反应在结直肠癌发展中的作用。虽然研究宿主的先天传感器提供了丰富的信息，但确定微生物组在CRC发展中的作用将需要一种更直接的方法，即干扰微生物群落并测量微生物和宿主的后果。本应用的目的是确定选择性共生菌群如何促进Il10-/-小鼠CRC的发展。我们假设特定的细菌实体通过表达微生物基因毒性产物促进结直肠癌的发展，导致宿主基因组不稳定性增强和肿瘤病变的形成。我们根据我们的初步发现提出了这一假设，表明特定的细菌分类群在荷瘤小鼠中扩大，而这些细菌分类群在无瘤小鼠中未被检测到。此外，尽管大肠杆菌NC101 （E. coli）和粪肠球菌（E. faecalis）单相关Il10-/-小鼠的结肠炎严重程度在组织学和分子水平上相似，但与粪肠球菌相比，大肠杆菌NC101组的肿瘤数量明显增加。最后，我们在大肠杆菌NC-101中发现了pks基因组岛，它编码一组聚酮合成酶基因，这些基因已被证明可以产生一种基因毒性产物——大肠杆菌蛋白。这个基因组岛诱导细胞周期阻滞和组蛋白2ax丝氨酸139磷酸化（?H2AX）。我们计划通过以下具体目标来检验我们的中心假设并实现本应用程序的总体目标。1)明确炎症对微生物群落结构和功能的影响；2)确定大肠杆菌NC101介导结直肠癌发生发展的机制。在这些研究完成后，我们希望能够确定与结直肠癌发展相关的微生物群落，并确定微生物基因产物，增强对这种病理的易感性。由于结直肠癌是美国癌症死亡的第二大原因，也是长期溃疡性结肠炎和克罗恩结肠炎的主要并发症，我们的研究结果将是重要的，因为它们将确定新的途径，可以预防/治疗炎症性结直肠癌。此外，从宏基因组研究中获得的基础知识有望推动CRC研究的总体领域向前发展。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third most common form of cancer in men and women in the United States and the second leading cause of cancer-related death. Chronic intestinal inflammation has been identified as an important risk factor for the development of colorectal cancer and consequently individuals suffering from inflammatory bowel diseases (IBD) are at high risk. The role of the microbiota in the development of CRC has not been clearly defined. To date, research has largely focused on the role of innate sensors and associated host responses in the development of colorectal cancer. While studying innate sensors in the host is informative, establishing the role of the microbiome in the development of CRC will require a more direct approach that perturbs the microbial community and measures the consequences for both microbes and host. The objective of the present application is to determine how selective group of commensal bacteria promote development of CRC in Il10-/- mice. We hypothesize that specific bacterial entities promote the development of CRC through expression of microbial genotoxic products, resulting in enhanced host genomic instability and formation of neoplastic lesions. We have formulated this hypothesis based on our preliminary findings showing that specific bacterial taxa expand in tumor-bearing mice, whereas these were not detected in tumor-free mice. Furthermore, although colitis severity at the histological and molecular level is similar between Escherichia coli NC101 (E. coli) and Enterococcus faecalis (E. faecalis) monoassociated Il10-/- mice, tumor numbers were strongly enhanced in the E. coli NC101 group compared to E. faecalis. Finally, we identified the pks genomic island in E.coli NC-101, which encodes a set of polyketide-synthetase genes that have been shown to produce a genotoxic product, colibactin. This genomic island induces cell cycle arrest and histone2AX serine 139 phosphorylation (?H2AX). We plan to test our central hypothesis and fulfill the overall objective of this application with the following specific aims. 1) Identify the impact of inflammation on microbial community structure and function and 2) Determine the mechanisms of E.coli NC101- mediated development of colorectal cancer. At the completion of these studies, we expect to have identified the microbial communities associated with the development of CRC and determined microbial gene products that enhanced susceptibility to this pathology. Since CRC is the second leading cause of cancer death in the U.S. and is a major complication of long standing ulcerative colitis and Crohn's colitis, our findings will be important because they will identify novel pathways that can be targeted to prevent/treat inflammation-induced CRC. In addition, the basic knowledge gained from metagenomic studies is expected to move the general field of CRC research forward.