The Role of the Metaplastic Microenvironment in Barrett's Esophagus

化生微环境在巴雷特食管中的作用

• 批准号: 10381174
• 负责人: Julian Abrams
• 金额: $ 22.39万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381174
• 关键词: Acids; Address; Adenocarcinoma; Bacteria; Barrett Esophagus; Cancer Etiology; Cell Differentiation process; Cells; Cessation of life; Chronic; Deoxycholic Acid; Development; Disease; Dysplasia; Early identification; Enterobacteriaceae; Epithelial; Esophageal Adenocarcinoma; Esophageal Squamous Cell Carcinoma; Esophagus; Fibroblasts; Gastroesophageal reflux disease; Goblet Cells; Immune; Incidence; Individual; Injury; Intestines; Lesion; Malignant neoplasm of esophagus; Metaplasia; Monitor; Mucous body substance; Parents; Patients; Phenotype; Play; Production; Risk Factors; Role; Signal Transduction; Stratified Squamous Epithelium; United States; Western Europe; carcinogenicity; cytokine; improved; microbiome; notch protein; parent grant; response; tumorigenesis; tumorigenic

Project Summary Esophageal Cancer is a leading cause of cancer death worldwide. The two subtypes include Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC). In the United States (US) and Western Europe, EAC is the more common subtype. In the US this year over 16,000 individuals are expected to die from EAC. To improve survival, identification of its precursor lesion, Barrett’s Esophagus is important. Barrett’s Esophagus, i.e. intestinal metaplasia of the esophagus, occurs in the setting of chronic gastroesophageal reflux (GERD) when the normal stratified squamous epithelium of the esophagus is replaced by an intestinal type. Early Identification of this lesion leads to regular surveillance to monitor for progression to dysplasia and adenocarcinoma. Some patients, however, never progress to EAC while others do. Recently, in our lab we have identified that infiltrating fibroblasts and other immune cells play an important role in promoting tumorigenesis. The role and phenotype of infiltrating fibroblasts and other immune cells in promoting progression from metaplasia to dysplasia is unclear. In this proposal we seek to clarify the role of the metaplastic microenvironment in promoting this progression to dysplasia and adenocarcinoma. In particular, we seek to understand how activated fibroblasts interact with the esophageal microbiome and deoxycholaic acid in the gastro-esophageal refluxate. We hypothesize that specific, activated fibroblast secrete pro-tumorigenic cytokines promoting progression to dysplasia in the context of deoxycholic acid and altered esophageal microbiome induced by injury from gastro-esophageal refluxate. This hypothesis will be pursued through the following inter-related specific aims: 1.) To assess the effect of DCA on Barrett’s Esophagus Associated Fibroblasts and 2.) To assess the effect of Enterobacteriaceae on Barrett’s Esophagus Associated Fibroblasts. The parent grant addresses the hypothesis that deoxycholic acid (DCA) in gastro-esophageal refluxate induces Notch signaling in BE, decreasing goblet cell differentiation and mucus production. This in turn increases the interaction of pro-carcinogenic bacteria with the underlying epithelium, promoting the development of EAC. However, the parent R01 does not address the relationship between DCA, Notch signaling, and the microbiome with the BE-associated microenvironment. This proposal address this critical gap.

项目概要 食管癌是全球癌症死亡的主要原因，这两种亚型包括。 食管鳞状细胞癌（ESCC）和食管腺癌（EAC）。 美国 (US) 和西欧，EAC 是今年在美国更常见的亚型。 预计将有超过 16,000 人死于 EAC。为了提高生存率，需要对其进行识别。 前驱病变，巴雷特食管很重要，即肠道。 食管化生，发生在慢性胃食管反流（GERD）的情况下 当食管正常的复层鳞状上皮被肠壁取代时 早期识别这种病变需要定期监测以监测其进展情况。 然而，一些患者从未进展为 EAC，而另一些患者则从未进展为 EAC。 最近，在我们的实验室中，我们发现了浸润性成纤维细胞和其他免疫细胞。 浸润的作用和表型在促进肿瘤发生中发挥重要作用。 成纤维细胞和其他免疫细胞促进化生进展为不典型增生 在本提案中，我们试图阐明化生微环境在其中的作用。 我们特别寻求促进这种进展为不典型增生和腺癌。 了解活化的成纤维细胞如何与食道微生物组和脱氧胆酸相互作用 我们捕获了胃食管反流液中的特定活化成纤维细胞。 分泌促肿瘤细胞因子，促进发育不良的进展 胃食管损伤引起的脱氧胆酸和食管微生物群的改变 这一假设将通过以下相互关联的具体目标来实现：1.) 评估 DCA 对 Barrett 食管相关成纤维细胞的影响以及 2.) 评估 肠杆菌科对巴雷特食管相关成纤维细胞的影响。 格兰特提出了胃食管反流中的脱氧胆酸（DCA）的假设 在 BE 中诱导 Notch 信号传导，减少杯状细胞分化和粘液产生。 反过来又增加了致癌细菌与下面的上皮细胞的相互作用， 促进 EAC 的发展，但是母版 R01 并没有解决这种关系。 DCA、Notch 信号传导和微生物组与 BE 相关微环境之间的关系。 该提案解决了这一关键差距。