The role of esophageal myofibroblasts in alcohol related esophageal squamous cell carcinoma.

摘要 食道鳞状细胞癌是一种致命的恶性肿瘤，酒精是主要的危险因素。最重要的目标 这一R21建议的目的是了解人食管肌成纤维细胞(HEMF)在食管壁中的作用。 食管鳞癌的发生发展。我们假设暴露在酒精中的HEMF 为ESCC的发展提供宽松的环境。我们计划使用一个 结合2D和3D文化模式的具体目标如下(1)。确定酒精和酒精的影响 其代谢产物乙醛对HEMF增殖/凋亡、基因和分泌谱及其在HEMF中的作用 有无酸性胆盐。(2)。确定酒精处理的高强度电磁场在 酸性胆盐的存在/不存在对上皮细胞的增殖、分化、异型增生和 上皮-间充质转化和询问涉及信号通路。(3)。确定HEMF位置， 鳞状上皮内异型增生和食管鳞癌的增殖和基因组改变及其影响 在上皮细胞上。了解酒精对HEMF和HEMF-上皮相互作用的影响 不典型增生或浸润性癌将确定酒精增加食道风险的分子基础 并导致以允许的肿瘤微环境为治疗靶点的新方法。

ABSTRACT Esophageal squamous cell cancer is a deadly malignancy with alcohol a major risk factor. The overarching aim of this R21 proposal is to understand the role of human esophageal myofibroblasts (HEMFs) in the development of esophageal squamous cell carcinoma. We hypothesize that HEMFs exposed to alcohol provide a permissive environment for development of ESCC. We plan to test our hypothesis using a combination of 2D and 3D culture models in the following specific aims (1). Determine the effect of alcohol and its metabolite acetaldehyde on HEMF proliferation/apoptosis, gene and secretory profile, and function in the presence and absence of acidic bile salts. (2). Define effects of alcohol treated HEMFs in the presence/absence of acidic bile salts on overlying epithelial proliferation, differentiation, dysplasia and epithelial-mesenchymal transition and interrogate involved signaling pathways. (3). Determine HEMF location, proliferation, and genomic alterations in squamous intraepithelial dysplasia and ESCC and determine the effect on the epithelium. Understanding the effect of alcohol on HEMFs and HEMF-epithelial interactions prior to dysplasia or invasive cancer will identify the molecular basis by which alcohol increases risk for esophageal cancer and lead to novel approaches that therapeutically target a permissive tumor microenvironment.