Reflux-Induced Epithelial-Mesenchymal Transition in Benign Barrett's Esophagus

良性巴雷特食管反流诱导的上皮间质转化

• 批准号: 9148175
• 负责人: RHONDA F SOUZA
• 金额: $ 8.73万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2017-01-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9148175
• 关键词: Ablation; Acids; Acute; Adenocarcinoma; Adult; Adverse effects; American; Barrett Esophagus; Benign; Bile Acids and Salts; Binding; Cancer Etiology; Cancer Patient; Cell Line; Cells; Cessation of life; Characteristics; Creation of jejunostomy; Data; Development; Dysplasia; Endoscopic Biopsy; Epithelial; Epithelial Cells; Esophageal; Esophageal Adenocarcinoma; Esophagus; Exhibits; Exposure to; Failure; Gastric Juice; Gastroesophageal reflux disease; Gland; Hypoxia Inducible Factor; In Vitro; Inflammation; Interruption; Intestinal Metaplasia; Intestines; KDR gene; Lamina Propria; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Medical; Mesenchymal; Metaplasia; Metaplastic; Modeling; Mucous Membrane; Nuclear; Patients; Peptic Esophagitis; Procedures; Process; Production; Proton Pump Inhibitors; Public Health; Radiofrequency Interstitial Ablation; Rattus; Reactive Oxygen Species; Recurrence; Reflux; Risk Factors; Role; Signal Transduction; Source; Squamous Epithelium; Telomerase; Vascular Endothelial Growth Factors; Wound Healing; autocrine; bile salts; cell motility; in vivo; neoplastic; neoplastic cell; prevent; programs; tumor; tumor progression

Project Summary It has been estimated that 5.6% of adult Americans have Barrett’s esophagus (BE), a major risk factor for esophageal adenocarcinoma. To prevent this cancer, patients with BE are advised to have regular endoscopic surveillance for dysplasia, and to have that dysplasia treated with radiofrequency ablation (RFA). Unfortunately, surveillance has not prevented deaths from esophageal cancer, and Barrett’s metaplasia recurs frequently after RFA. Surveillance failures and metaplasia recurrences might be due to subsquamous intestinal metaplasia (SSIM), a condition in which metaplastic glands are located in the lamina propria under a layer of squamous epithelium that hides them from the endoscopist and shields them from destruction by RFA. SSIM initially was considered a side effect of endoscopic ablation, but recent studies show that SSIM is present in the large majority of Barrett’s patients who have not had ablation procedures. This highly prevalent SSIM might be the source of tumors missed by endoscopic surveillance, and the nidus for recurrent metaplasia after RFA. Thus, SSIM appears to be a frequent and important condition that limits the efficacy of endoscopic surveillance for the millions of patients with BE, and that thwarts endoscopic attempts to eradicate BE and prevent its progression to cancer. Epithelial-mesenchymal transition (EMT) is the process in which epithelial cells acquire mesenchymal characteristics including cell migration. In BE, EMT could enable metaplastic Barrett’s epithelial cells to migrate into the lamina propria underneath adjacent squamous epithelium, resulting in SSIM. In our rat model in which we induce reflux esophagitis by creating an esophago-jejunostomy, our preliminary data strongly suggest that jejunal epithelial cells adjacent to ulcerated esophageal squamous mucosa undergo EMT, which contributes to the development of a columnar-lined esophagus with features of Barrett’s metaplasia including SSIM. Gastroesophageal reflux causes esophageal inflammation and production of reactive oxygen species, conditions that can activate hypoxia inducible factors (HIFs). Our preliminary data show that Barrett’s epithelial cells exposed to acid and bile salts exhibit a strong and sustained increase in nuclear HIF-1α and HIF-2α. In patients with BE, we also show that HIF-1α and HIF-2α levels in their Barrett’s metaplasia rise when the esophagus is perfused with acid or bile salts. HIFs can promote EMT by causing cells to secrete vascular endothelial growth factor (VEGF), which binds the cells’ VEGF receptors in an autocrine fashion to induce VEGF signaling that triggers EMT. Our preliminary data show that acid and bile salts induce autocrine VEGF signaling and EMT features in Barrett’s cell lines. Therefore, we hypothesize that reflux-induced activation of HIFs in Barrett’s epithelial cells causes VEGF secretion with autocrine VEGF signaling, which initiates the EMT program and causes SSIM. The aims of this study are to elucidate the mechanism(s) whereby acid and bile salts activate HIFs to cause VEGF production, and to explore the role of autocrine VEGF signaling in the EMT program induced by acid and bile salts in Barrett’s cells in vitro, and in BE patients with reflux esophagitis.

项目摘要 据估计，有5.6％的成年美国人患有巴雷特的食管（BE），这是一个主要的危险因素 食管腺癌。为了防止这种癌症，建议患有定期内窥镜患者 对发育不良的监测，并患有射频消融（RFA）治疗的发育异常。很遗憾， 监测并未阻止食管癌死亡，而巴雷特的变质症经常出现 RFA。监视失败和变质回报可能是由于肠道肠上流过渡造成的 （SSIM），在鳞状层下定位的条件 上皮使他们脱离内窥镜，并使他们免受RFA的破坏。 SSIM最初是 被认为是内窥镜消融的副作用，但最近的研究表明，大多数人都存在SSIM 巴雷特（Barrett）的患者没有消融程序。这种非常普遍的SSIM可能是 内窥镜监测遗漏的肿瘤和RFA后复发性化生的Nidus。那就出现了 成为一种经常且重要的条件，限制了内窥镜监视的效率 患有BE的患者，并阻止内窥镜进行放射性化的尝试并防止其发展为癌症。 上皮间质转变（EMT）是上皮细胞获得间质细胞的过程 包括细胞迁移的特征。在be中，EMT可以使化合物Barrett的上皮细胞迁移 进入相邻正方形上皮下方的椎板过度，导致SSIM。在我们的大鼠模型中 我们的影响反映了食管炎通过创建食道 - jejunostomy，我们的初步数据强烈表明 空肠上皮细胞与溃疡性食道鳞状粘膜相邻，经历EMT，这有助于 开发了圆柱衬里的食管，其特征是Barrett的化学特征，包括SSIM。 胃管反射X会导致食道注射和活性氧的产生， 可以激活缺氧诱发因子（HIF）的疾病。我们的初步数据表明，巴雷特的上皮 暴露于酸和胆汁销售的细胞暴露了核HIF-1α和HIF-2α的强劲增长。在 患有BA的患者，我们还表明，当Barrett的化生中HIF-1α和HIF-2α水平上升时 食道灌注酸或胆汁盐。 HIF可以通过引起细胞秘密血管来促进EMT 内皮生长因子（VEGF），它以自分泌方式结合细胞的VEGF受体以诱导 VEGF信号触发EMT。我们的初步数据表明，酸和胆汁沙拉会诱导自分泌VEGF Barrett细胞系中的信号传导和EMT特征。因此，我们假设反射引起的激活 Barrett上皮细胞中的HIF通过自分泌VEGF信号传导引起VEGF分泌，这引发了EMT 程序并导致SSIM。这项研究的目的是阐明酸和胆汁的机制 盐激活HIF引起VEGF的产生，并探索Autocrine VEGF信号在EMT中的作用 Barrett细胞中酸和胆汁盐在体外以及反射X炎患者中诱导的程序。