Molecular pathogenesis of intestinal serrated polyps

 描述(申请人提供)：结肠癌是美国第三种最常见的癌症，也是癌症相关死亡的第三大原因。多年来，人们认为结直肠癌(CRC)是由晚期腺瘤性息肉演变而来的。然而，近年来有令人信服的证据表明，相当大比例的CRC是在锯齿状息肉的一小部分中发展起来的，其机制与腺瘤-癌的发展进程不同。结直肠最常见的两种上皮性息肉是腺瘤和锯齿状息肉。锯齿状息肉的形态特征是隐窝上皮呈锯齿状展开。目前，锯齿状息肉可分为四大类：增生性息肉、固定性锯齿状腺瘤、传统锯齿状腺瘤和混合性锯齿状息肉。锯齿状息肉在肠道中有明显的亚型依赖位置。增生性息肉最常见于左半结肠和直肠，而无柄锯齿状腺瘤多见于右半结肠。从历史上看，增生性息肉被认为几乎没有恶性潜能。然而，这种观点最近发生了变化，因为有证据表明，增生性息肉表现出在肿瘤性病变中出现的分子特征，如微卫星不稳定(MSI)、DNA甲基化异常以及BRAF和KRAS基因突变。除了KRAS和BRAF突变，我们的工作表明，EGFR受体的激活也促进了锯齿状息肉的发展。我们开发了一种新的小鼠锯齿状息肉模型，它代表了人类锯齿状息肉的一个子集，它独立于BRAF或KRAS的激活突变而出现，而是由于EGFR受体活性增加而发生。这一模型在形态和生化上与人类锯齿状息肉相似。引人注目的是，与人类锯齿状息肉相似，HBUS小鼠的锯齿状息肉在肠道的特定位置发育，并依赖于遗传和环境因素。在这个提案中，我们将调查这样一个环境因素，即微生物区系，是如何影响锯齿状息肉的发展的。目的一是对致病微生物(S)的鉴定。目标2旨在了解微生物区系如何影响宿主，以及这如何导致锯齿状息肉的发展。微生物组(J.Faith和J.C.Clemente，西奈)、微RNA生物学(B.Brown，西奈)、甲基组(Daniel Carvalho，多伦多)和病理学(Noam Harpaz，西奈)的专家团队将协助我们进行这些研究。

 DESCRIPTION (provided by applicant): Colon cancer is the third most common cancer and the third leading cause of cancer-related mortality in the United States. For many years it was believed that colorectal cancers (CRC) evolved from advanced adenomatous polyps. In recent years, however, convincing evidence has emerged that a significant proportion of CRC develops within a small subset of serrated polyps, through a mechanism that is different from those responsible for the adenoma-carcinoma developmental progression. The two most common epithelial polyp in the colorectum are adenomas and serrated polyps. Serrated polyps are morphologically characterized by a "saw-toothed" unfolding of the crypt epithelium. Currently, serrated polyps are grouped in 4 major categories: hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed serrated polyps. Serrated polyps have a striking subtype dependent location in the gut. Hyperplastic polyps are most frequently found in the left colon and rectum, while sessile serrated adenomas are usually found in the right colon. Historically, hyperplastic polyps have been considered to have little or no malignant potential. This view, however, has changed recently, as evidence has emerged that hyperplastic polyps display molecular features seen in neoplastic lesions, such as microsatellite instability (MSI), aberrant DNA methylation, and mutations in BRAF and KRAS genes. In addition to KRAS and BRAF mutations, our work suggests that activation of the EGFR receptor also promotes the development of serrated polyps. We have developed a novel model for serrated polyps in mice that represents a subset of human serrated polyps that arise independent of activating mutations in BRAF or KRAS, but rather occur due to increased activity of the EGFR receptor. This model presents morphological and biochemical similarities to serrated polyps in humans. Strikingly, similar to human serrated polyps, serrated polyps in HBUS mice develop in a specific location of the gut and are dependent on both genetic and environmental factors. In this proposal we will investigate how one such an environmental factor, namely the microbiota, affects the development of serrated polyps. Aim 1 is focused on the identification of the causative organism(s). Aim 2 is aimed at understanding how the microbiota affects the host and how this leads to the development of serrated polyps. A team of experts in microbiome (J. Faith, and J.C. Clemente, Sinai), microRNA biology (B. Brown, Sinai), methylome (Daniel Carvalho, Toronto) and pathology (Noam Harpaz, Sinai) will assist us in these studies.