Role of Bacteria in Colitis-Associated Colon Cancer

描述(申请人提供)：结直肠癌(CRC)是美国男性和女性的第三种最常见的癌症，也是与癌症相关的死亡的第二大原因。慢性肠炎已被认为是结直肠癌发生的重要危险因素，因此炎症性肠病(IBD)患者处于高危状态。微生物区系在结直肠癌发展中的作用尚未明确界定。到目前为止，研究主要集中在先天性传感器和相关的宿主反应在结直肠癌发生发展中的作用。虽然研究宿主中的固有传感器是有意义的，但要确定微生物组在结直肠癌发展中的作用，将需要一种更直接的方法来扰乱微生物群落，并衡量对微生物和宿主的后果。本申请的目的是确定选择性共生菌群如何促进IL10-/-小鼠结直肠癌的发展。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，导致宿主基因组的不稳定性增强和肿瘤病变的形成。我们提出这一假设是基于我们的初步发现，即特定的细菌分类群在有肿瘤的小鼠中扩张，而在无肿瘤的小鼠中没有检测到。此外，尽管在组织和分子水平上结肠炎的严重程度在大肠杆菌NC101和粪肠球菌(粪肠球菌)单一相关的IL10-/-小鼠之间是相似的，但与粪肠球菌相比，大肠杆菌NC101组的肿瘤数量显著增加。最后，我们在E.ColiNC-101中发现了PKS基因组岛，该岛编码一组聚酮合成酶基因，已被证明产生一种遗传毒性产物Colibactin。这个基因组岛诱导细胞周期停滞和组蛋白2AX丝氨酸139磷酸化(H_2AX)。我们计划测试我们的中心假设，并实现此应用程序的总体目标，具体目标如下。1)确定炎症对微生物群落结构和功能的影响；2)确定E.ColiNC101介导的结直肠癌发生的机制。在这些研究完成后，我们预计已经确定了与结直肠癌发生相关的微生物群落，并确定了提高这种病理易感性的微生物基因产物。由于结直肠癌是美国癌症死亡的第二大原因，也是长期存在的溃疡性结肠炎和克罗恩结肠炎的主要并发症，我们的研究结果将具有重要意义，因为它们将确定可以作为预防/治疗炎症诱导的结直肠癌的靶向的新途径。此外，从元基因组学研究中获得的基础知识有望推动CRC研究的一般领域向前发展。

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.