The impact of exposure to allergic inflammation on esophageal carcinogenesis

接触过敏性炎症对食管癌发生的影响

• 批准号: 10112399
• 负责人: Kelly A Whelan
• 金额: $ 22.23万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112399
• 关键词: Allergic; Allergic inflammation; Antitumor Response; Apoptosis; Apoptotic; Basal Cell; Bioinformatics; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Patient; Cell Compartmentation; Cell Death; Cells; Chronic; Clinical; Coculture Techniques; Data; Development; Diagnosis; Eosinophilia; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Esophageal Adenocarcinoma; Esophageal Neoplasms; Esophagitis; Esophagus; Event; Exposure to; Future; Gastroesophageal reflux disease; Goals; Hypersensitivity; IgE; Immune; Immune response; Inflammation; Inflammatory; Investigation; Knowledge; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Mediator of activation protein; Modeling; Molecular; Monitor; Mononuclear; Mus; Organ; Outcome; Patient-Focused Outcomes; Patients; Peptic Esophagitis; Plant Roots; Population; Population Study; Prevention therapy; Reflux; Risk Factors; Signal Transduction; System; Testing; Tumor Cell Line; antitumor effect; base; cancer prevention; cancer risk; carcinogenesis; clinical care; eosinophil; epidemiologic data; epidemiology study; esophageal cancer prevention; esophageal carcinogenesis; food allergen; genetic signature; improved; in vivo; mortality; mouse model; neoplastic cell; novel; novel strategies; peripheral blood; pre-clinical; progenitor; single-cell RNA sequencing; translational impact

Project Summary Esophageal cancer is the eighth most common cancer and sixth leading cause of cancer mortality worldwide. Chronic reflux-associated esophagitis, termed gastroesophageal reflux disease (GERD), is a primary risk factor for development of esophageal adenocarcinoma. Eosinophilic esophagitis (EoE) represents food allergen-mediated esophagitis characterized by esophageal eosinophilia. In contrast to patients with reflux esophagitis, epidemiological data indicates that EoE patients fail to develop esophageal cancer despite the presence of chronic esophageal inflammation. A negative correlation between allergic inflammation and cancer risk has been identified in a variety of organs via population-based studies; however, functional investigations are necessary to define the relationship between allergy and cancer as well as to determine the feasibility of approaches for leveraging allergic inflammation to improve clinical outcomes in cancer patients. To examine the relationship between EoE and cancer, we paired murine models of the two conditions. Our robust preliminary data indicate that exposure to EoE inflammation limits esophageal carcinogenesis in vivo. We hypothesize that EoE inflammation limits esophageal carcinogenesis by activating anti-tumor responses in the immune and epithelial cell compartments. We will test this hypothesis by pursuing the following Specific Aims: Aim 1: Identify the immune-mediated mechanisms responsible for tumor cell apoptosis induced by EoE inflammation. Aim 2: Delineate the impact of EoE inflammation upon esophageal epithelial cells in the context of carcinogenesis. These studies provide the first functional investigation of the relationship between EoE and esophageal cancer with the potential to unveil novel mechanisms for targeting the allergic immune response and/or allergy-mediated esophageal epithelial fate decisions to improve clinical care for cancer patients. These developmental R21 studies will identify the direct cellular/molecular mechanisms through which the EoE influences the epithelial and immune cell compartments to limit esophageal carcinogenesis. A future R01 proposal will aggressively pursue identified mechanisms in preclinical and clinical models to meet our long- term goal of defining novel strategies for improving esophageal cancer prevention, diagnosis, monitoring, and therapy. As a negative association between allergic inflammation and cancer has been identified in various organs, findings from this study may have broad implications for cancer prevention and therapy.

项目概要 食管癌是全球第八大常见癌症，也是第六大癌症死亡原因。 慢性反流相关食管炎，称为胃食管反流病 (GERD)，是主要风险 食管腺癌发生的因素。嗜酸性粒细胞性食管炎（EoE）代表食物 以食管嗜酸性粒细胞增多为特征的过敏原介导的食管炎。与反流患者相比 食管炎，流行病学数据表明，EoE 患者尽管接受了食管炎治疗，但并未发展为食管癌。 存在慢性食管炎症。过敏性炎症与癌症之间呈负相关 通过基于人群的研究已确定了多种器官的风险；然而，功能研究 对于定义过敏和癌症之间的关系以及确定治疗的可行性是必要的 利用过敏性炎症改善癌症患者临床结果的方法。检查 为了研究 EoE 与癌症之间的关系，我们将这两种情况的小鼠模型配对。我们稳健的 初步数据表明，暴露于 EoE 炎症可限制体内食管癌的发生。我们 假设 EoE 炎症通过激活食管中的抗肿瘤反应来限制食管癌的发生 免疫细胞和上皮细胞区室。我们将通过追求以下具体目标来检验这一假设： 目标 1：确定 EoE 诱导肿瘤细胞凋亡的免疫介导机制 炎。目标 2：描述 EoE 炎症对食管上皮细胞的影响 的致癌作用。这些研究首次对 EoE 和 食管癌有可能揭示针对过敏性免疫反应的新机制 和/或过敏介导的食管上皮命运决定，以改善癌症患者的临床护理。这些 发育 R21 研究将确定 EoE 的直接细胞/分子机制 影响上皮细胞和免疫细胞区室以限制食管癌的发生。未来的R01 该提案将积极寻求临床前和临床模型中已确定的机制，以满足我们的长期需求 确定改善食管癌预防、诊断、监测和治疗的新策略的长期目标 治疗。由于过敏性炎症与癌症之间存在负相关性，已在多种研究中得到证实。 器官，这项研究的结果可能对癌症的预防和治疗具有广泛的影响。