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

项目概要 巴雷特食管 (BE) 是正常鳞状食管上皮的替代物 它是由于慢性胃酸和胆汁反流损伤而发生的。 食管腺癌 (EAC) 是一种最重要的危险因素。 发病率以惊人的速度上升，因此，提高了我们对BE发病机制的了解。 其向 EAC 的进展是一项关键的研究当务之急，这是近期基因组研究的一个重要教训。 该团队的研究表明，BE 中存在许多潜在致病性体细胞突变 那些没有进展为不典型增生或癌症的人的上皮细胞，强调了过程的重要作用 除了促进疾病发生和进展的基因组突变之外，我们还重点关注其关键作用。 肿瘤微环境在 BE 和 EAC 发病机制中的作用，其目标是 我们提供了涉及渗透子集的新的、令人信服的数据。 在相互增强的信号通路的互连网络中激活成纤维细胞和免疫细胞 我们发现这些肿瘤促进细胞与BE上皮细胞一起增强癌发生。 BE 微环境中的种群是理解 BE 如何以及为何发展为 EAC 的关键 这些细胞的特征和调控途径将作为开发的基础 筛选和治疗的新方法将通过以下方式进行。 相互关联的具体目标： 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) 证明癌症分泌的 IL-6 是如何相关的。 成纤维细胞和 TP53 突变上皮促进 BE 发病机制和进展为 EAC 3) 检查。 骨髓源性抑制细胞 (MDSC) 和调节性 T 细胞 (TReg) 对 BE 进展的影响 给 EAC 的总结和