The impact of exposure to allergic inflammation on esophageal carcinogenesis

项目摘要 食管癌是世界范围内第八大最常见的癌症和第六大癌症死亡原因。 慢性反流相关性食管炎，称为胃食管反流病（GERD），是一个主要的风险 食管腺癌的发展因素。嗜酸性食管炎（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患者未能发展食管癌，尽管 存在慢性食管炎。过敏性炎症与癌症之间的负相关性 通过基于人群的研究，已在多种器官中确定了风险;然而，功能研究 是必要的，以确定过敏和癌症之间的关系，以及确定的可行性 利用过敏性炎症改善癌症患者临床结果的方法。审查 为了研究EoE和癌症之间的关系，我们将两种情况的小鼠模型配对。我们强大 初步数据表明暴露于EoE炎症限制了体内食管癌的发生。我们 假设EoE炎症通过激活EoE中的抗肿瘤反应来限制食管癌的发生， 免疫和上皮细胞区室。我们将通过追求以下具体目标来检验这一假设： 目的1：探讨EoE诱导肿瘤细胞凋亡的免疫机制 炎症目的2：描述EoE炎症对食管上皮细胞的影响， 致癌作用。这些研究提供了第一个功能性调查之间的关系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 R21发育研究将确定EoE发生的直接细胞/分子机制， 影响上皮和免疫细胞区室以限制食管癌发生。未来R 01 该提案将积极寻求在临床前和临床模型中确定的机制，以满足我们的长期需求， 长期目标是确定改善食管癌预防、诊断、监测和治疗的新策略， 疗法由于过敏性炎症和癌症之间的负相关性已经在各种研究中得到证实， 这项研究的发现可能对癌症预防和治疗具有广泛的意义。

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.