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: 10183179
• 负责人: Anil K Rustgi
• 金额: $ 19.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183179
• 关键词: 3-Dimensional; 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; Esophageal Adenocarcinoma; Esophageal injury; Esophagus; Evolution; Fibroblasts; Flow Cytometry; Foundations; Gastroesophageal reflux disease; Genomics; Health; Human; Immune; Immune response; Incidence; Infiltration; Inflammation; Inflammation Mediators; Interleukin 6 Receptor; Interleukin-6; Internet; Intestines; Lipids; Malignant Neoplasms; Measures; Mediator of activation protein; Modeling; Mus; Mutation; Myeloid-derived suppressor 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; Surface; TP53 gene; Testing; Therapeutic; Tissues; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; 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; tissue injury; 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

项目总结