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

食管肌成纤维细胞在酒精相关食管鳞状细胞癌中的作用。

• 批准号: 10371074
• 负责人: Anisa Shaker
• 金额: $ 19.59万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371074
• 关键词: 3-Dimensional; Acetaldehyde; Address; Agar; Alcohol consumption; Alcohols; Apoptosis; Behavior; Biological Assay; Biological Process; Cell Line; Characteristics; DNA Sequence Alteration; Development; Dysplasia; Environment; Epithelial; Esophageal Intraepithelial Neoplasia; Esophageal Squamous Cell Carcinoma; Esophagus; Esophagus motility; Gene Proteins; Genes; Growth Factor; Human; Hypoxia; IL6 gene; Impairment; In Vitro; Inferior esophageal sphincter structure; Injury; Intervention; Intraepithelial Neoplasia; Lamina Propria; Lead; Literature; Location; MAPK3 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Mesenchymal; Modeling; Molecular; Morphology; Myofibroblast; Neoplasm Metastasis; Paracrine Communication; Paraffin Embedding; Pathology; Preventive; Quantitative Reverse Transcriptase PCR; Reflux; Research; Risk; Risk Factors; Role; STAT3 gene; Secondary to; Signal Pathway; Squamous Epithelium; Survival Rate; Testing; Therapeutic; Tissues; Transcript; Work; alcohol effect; alcohol exposure; alcohol measurement; angiogenesis; bile salts; cancer invasiveness; carcinogenicity; cell growth; cell growth regulation; cytokine; esophageal squamous cell cancer; exposed human population; genomic profiles; intraepithelial; laser capture microdissection; novel; novel therapeutic intervention; paracrine; pressure; response; therapeutic target; three dimensional cell culture; tumor; tumor microenvironment; tumorigenic

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.

摘要 食管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。首要目标 这项R21提案的目的是了解人食管肌成纤维细胞（HEMF）在 食管鳞状细胞癌的发展我们假设暴露于酒精的HEMF 为经济、社会和文化权利的发展提供一个宽松的环境。我们计划用一个 2D和3D文化模型的组合，具体目标如下（1）。确定酒精的影响， 其代谢物乙醛对HEMF增殖/凋亡、基因和分泌谱的影响，以及在 存在和不存在酸性胆汁盐。（二）、确定酒精处理的HEMF在 存在/不存在酸性胆汁盐对上覆上皮增殖、分化、发育异常和 上皮-间质转化和interrogate参与的信号通路。（三）、确定HEMF位置， 鳞状上皮内异型增生和ESCC中的增殖和基因组改变， 在上皮上。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症将确定酒精增加食管癌风险的分子基础。 癌症，并导致新的方法，治疗靶向一个宽容的肿瘤微环境。