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; 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 巴雷特的食道（BE）是正常鳞状食管上皮的替代品 无关紧要的柱状上皮。它是响应于慢性酸和胆汁反射X损伤而发生的 食道是食道腺癌（EAC）的最重要的危险因素，一种疾病 发病率以惊人的速度上升。因此，提高我们对BE发病机理的理解 它的发展是一项重要的研究。最近的基因组研究的主要课程部分领导 该团队证明了BE中存在许多潜在的病原体体细胞突变 那些不发展发育异常或癌症的人的上皮，强调了过程的重要作用 除了促进疾病发作和进展的基因组突变。在这里，我们专注于关键角色 BE和EAC发病机理的肿瘤微环境通过 集成和完整。我们提供新的和引人入胜的数据含义的一部分渗透 激活的成纤维细胞和免疫细胞在相互连接的相互加固信号通路的网络中 与增强癌变的上皮细胞。我们假设这些促进肿瘤的细胞 BE微环境中的种群是了解如何以及为什么发展到EAC和为什么的关键 这些细胞和调节途径的表征将成为发展的基础 筛查和治疗的新方法。该假设将通过以下来提出 相互关联的特定目的：1）确定免疫细胞和成纤维细胞的性质和功能 存在于人类和EAC患者中。 2）证明IL-6如何与癌症相关的分泌 成纤维细胞和TP53突变体上皮促进了发病机理和向EAC的发展。 3）检查 髓样衍生的抑制细胞（MDSC）和调节性T细胞（TREG）对BE的进展 到EAC。摘要和