The Role of the Metaplastic Microenvironment in Barrett's Esophagus

项目摘要 食管癌是世界范围内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）。在 美国（US）和西欧，EAC是更常见的亚型。今年在美国 预计将有超过16，000人死于EAC。为了提高生存率， Barrett食管是重要的前驱病变。Barrett食管，即肠 食管化生，发生在慢性胃食管反流（GERD）的背景下 当食管的正常复层鳞状上皮被肠上皮替代时， 类型.早期发现这种病变导致定期监测，以监测进展至 异型增生和腺癌。然而，一些患者从未进展到EAC，而另一些患者则没有进展到EAC。 做最近，在我们的实验室中，我们已经确定浸润的成纤维细胞和其他免疫细胞， 在促进肿瘤发生中起重要作用。浸润的作用和表型 成纤维细胞和其他免疫细胞在促进从化生到异型增生的进展中的作用， 不清楚在这个建议中，我们试图阐明化生微环境在 促进这种向发育异常和腺癌的进展。特别是，我们力求 了解活化的成纤维细胞如何与食管微生物组和脱氧胆酸相互作用 胃食管反流液中的酸。我们假设，特定的，活化的成纤维细胞 分泌促肿瘤发生细胞因子，促进发育异常的进展， 脱氧胆酸和胃食管损伤引起的食管微生物组改变 回流物。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Barrett食管相关成纤维细胞的影响。母 格兰特提出了胃食管反流中的脱氧胆酸（DCA） 诱导BE中的Notch信号传导，减少杯状细胞分化和粘液产生。这 反过来增加了促癌细菌与下面上皮的相互作用， 促进EAC的发展。然而，父R01不解决关系 DCA，Notch信号传导和微生物组与BE相关微环境之间的关系。 这项建议解决了这一关键差距。

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.