Molecular pathogenesis of intestinal serrated polyps

 描述（由申请人提供）：结肠癌是美国第三大常见癌症，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，很大一部分CRC发生在锯齿状息肉的一个小子集内，其机制与腺瘤-癌的发展过程不同。结肠直肠中最常见的两种上皮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，锯齿状息肉分为4大类：增生性息肉、无蒂锯齿状腺瘤、传统锯齿状腺瘤和混合锯齿状息肉。锯齿状息肉在肠道中具有显著的亚型依赖性位置。增生性息肉最常见于左结肠和直肠，而无蒂锯齿状腺瘤通常见于右结肠。从历史上看，增生性息肉被认为几乎没有或没有恶性潜力。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显示出肿瘤性病变的分子特征，如微卫星不稳定性（MSI），异常DNA甲基化以及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。我们已经开发了一种新的小鼠锯齿状息肉模型，该模型代表了人类锯齿状息肉的一个子集，这些息肉的产生不依赖于BRAF或KRAS中的激活突变，而是由于EGFR受体的活性增加而发生的。该模型与人类锯齿状息肉在形态和生化方面具有相似性。引人注目的是，与人类锯齿状息肉相似，HBUS小鼠中的锯齿状息肉在肠道的特定位置发育，并且依赖于遗传和环境因素。在这项提案中，我们将研究这样一个环境因素，即微生物群，如何影响锯齿状息肉的发育。目标1侧重于病原微生物的鉴定。目标2旨在了解微生物群如何影响宿主，以及这如何导致锯齿状息肉的发展。微生物组专家团队（J. Faith和J.C. Clemente，Sinai），microRNA生物学（B.布朗，西奈），甲基化（丹尼尔卡瓦略，多伦多）和病理学（诺姆哈帕兹，西奈）将协助我们在这些研究。

 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.