Project 2: Characterization of microenvironmental drivers of neoplasia in BE

项目 2：BE 肿瘤形成微环境驱动因素的表征

• 批准号: 9277751
• 负责人: Anil K Rustgi
• 金额: $ 24.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-12 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277751
• 关键词: Acids; Address; Apoptosis; Automobile Driving; Barrett Epithelium; Barrett Esophagus; Bile Reflux; Biological Models; Cancer Biology; Cell physiology; Cells; Chronic; Columnar Epithelium; DNA Sequence Alteration; Data; Disease; Disease Progression; Dysplasia; Engineering; Environment; Epithelial; Epithelial Cells; Epithelium; Esophageal; Esophageal Adenocarcinoma; Esophageal injury; Esophagus; Evolution; Fibroblasts; Flow Cytometry; Foundations; Genomics; Health; Human; Immune; Immune response; Incidence; Infiltration; Inflammation; Inflammation Mediators; Injury; Interleukin 6 Receptor; Interleukin-6; Internet; Intestines; Lipids; Malignant Neoplasms; Measures; Mediator of activation protein; Modeling; Mus; Mutation; Myelogenous; Myeloid Cells; Nature; Neoplasms; Oncogenes; Onset of illness; Organoids; Oxidative Stress; Pathogenesis; Pathogenicity; Patients; Phenotype; Population; Process; Production; Proteins; Reactive Oxygen Species; Regulatory Pathway; Regulatory T-Lymphocyte; Research; Risk Factors; Role; S100A8 gene; Signal Pathway; Somatic Mutation; Suppressor-Effector T-Lymphocytes; Surface; TP53 gene; Testing; Therapeutic; Tissues; Tumor Suppressor Proteins; carcinogenesis; carcinogenicity; cytokine; immune function; improved; innovation; insight; mutant; neoplastic; new therapeutic target; novel; novel marker; novel strategies; novel therapeutic intervention; public health relevance; response; screening; therapeutic target; tumor; tumor microenvironment

PROJECT SUMMARY Barrett’s esophagus (BE) is the replacement of the normal squamous esophageal epithelium with an incompletely intestinalized columnar epithelium. It occurs in response to chronic acid and bile reflux injury to the esophagus and is the most substantial risk factor for esophageal adenocarcinoma (EAC), a disease whose incidence has risen at an alarming rate. Therefore, improving our understanding of the pathogenesis of BE and its progression to EAC is a critical research imperative. A key lesson of recent genomic studies led in part by this team has demonstrated that many potentially pathogenic somatic mutations are present in the BE epithelium of those who do not progress to dysplasia or cancer, highlighting the important role of processes other than genomic mutations for promoting disease onset and progression. Here, we focus on the pivotal role of the tumor microenvironment in the pathogenesis of BE and EAC pathogenesis through aims that are integrated and complementary. We provide new and compelling data implicating a subset of infiltrating activated fibroblasts and immune cells in an interconnected web of mutually reinforcing signaling pathways with BE epithelial cells that enhances carcinogenesis. We hypothesize that these tumor-promoting cell populations in the BE microenvironment are key to understanding how and why BE progresses to EAC and that characterization of these cells and regulatory pathways will serve as a foundation for developing new approaches for screening and therapeutics. This hypothesis will be pursued through the following inter-related Specific Aims: 1) To determine the nature and function of the immune cells and fibroblasts present in human BE and EAC patients. 2) To demonstrate how IL-6 secreted by cancer associated fibroblasts and TP53 mutant epithelium promotes BE pathogenesis and progression to EAC. 3) To examine the effect of Myeloid-Derived Suppressor Cells (MDSC) and regulatory T-cells (TReg) on the progression of BE to EAC. Summary and

项目摘要 Barrett食管（BE）是正常鳞状食管上皮被一种 柱状上皮不完全钙化。它是对慢性酸和胆汁反流损伤的反应， 是食管腺癌（EAC）的最主要危险因素，EAC是一种 发病率以惊人的速度上升。因此，提高我们对BE发病机制的认识， 并且其向EAC的进展是至关重要的研究必要性。最近基因组研究的一个关键教训部分导致了 这个团队已经证明，许多潜在的致病性体细胞突变存在于BE中， 上皮的那些谁不进展到异型增生或癌症，强调过程的重要作用 而不是基因突变来促进疾病的发生和发展。在这里，我们关注的是 肿瘤微环境在BE和EAC发病机制中的作用， 整合和互补。我们提供了新的和令人信服的数据，涉及一个子集的渗透 活化的成纤维细胞和免疫细胞在相互加强的信号通路的互联网中 与BE上皮细胞，增强致癌作用。我们假设这些促癌细胞 BE微环境中的人群是理解BE如何以及为什么发展为EAC的关键， 这些细胞和调节途径的特征将作为开发 筛选和治疗的新方法。这一假设将通过以下几个方面加以探讨： 具体目的：1）确定免疫细胞和成纤维细胞的性质和功能 存在于人类BE和EAC患者中。2)为了证明癌症分泌的IL-6如何与 成纤维细胞和TP 53突变上皮促进BE发病机制和进展为EAC。3)审查 骨髓源性抑制细胞（MDSC）和调节性T细胞（TReg）对BE进展的影响 到EAC。总结和