Mechanisms of Tumorigenic Transformation of Barretts Esophagus

Barretts食管致瘤转化机制

• 批准号: 9248180
• 负责人: ALEXANDER I. ZAIKA
• 金额: $ 27.71万
• 依托单位: VANDERBILT UNIVERSITY 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: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248180
• 关键词: Mechanisms; Tumorigenic; Transformation; Barretts; Esophagus

PROJECT SUMMARY/ABSTRACT Esophageal adenocarcinoma (EAC) is a serious clinical problem due to its rapidly increasing incidence rate, and the limited treatment options currently available. This disease has now overtaken other histological types of esophageal tumors in the US. The major risk factor for EAC is gastroesophageal reflux disease (GERD), which affects 10 to 20% of the US population. Under conditions of GERD, esophageal cells are ex- posed to acidic gastric juice mixed with duodenal bile salts. The reflux exposure causes chronic inflammation, and excessive oxidative DNA damage, resulting in the accumulation of tumorigenic alterations and progression to EAC through Barrett's metaplasia (BE). However, the precise molecular events underlying the malignant transformation of esophageal cells remain poorly understood, thereby limiting the identification of targets for screening at risk patients and the development of new therapies for esophageal tumors. We have developed an innovative hypothesis to investigate tumorigenic transformation of esophageal cells in conditions of esophageal reflux injury. This hypothesis is supported by strong preliminary data from human tissues, animal models, and extensive in vitro studies. We have demonstrated that the 6Np73 protein plays a critical role in esophageal tumorigenesis by inhibiting key tumor suppressor proteins in Barrett's esophageal cells exposed to chronic gastroesophageal reflux. We have also identified pathological factors that lead to 6Np73 activation. We will build on these findings to further investigate the role played by 6Np73 and other members of the p53 protein family in the progression to esophageal adenocarcinoma. In aim 1, we will dissect the mechanisms of 6Np73 upregulation during progression to EAC. In aim 2, we will investigate esophageal tumorigenesis in vivo. We will employ novel mouse model of gastroesophageal reflux injury and esophageal organotypic cul- tures to recapitulate human GERD-associated pathology and dissect the function of 6Np73. These studies will be complemented with analyses of human esophageal precancerous and cancerous lesions. In aim 3, we will explore the biological functions in the regulation of oxidative DNA damage induced by gastroesophageal reflux. Our findings will have a strong impact on the understanding of multistep tumorigenesis associated with GERD and BE. Importantly, our results could help to reveal potential risk factors for esophageal tumor devel- opment and lay the groundwork for development of novel chemotherapeutic approaches in at risk patients with GERDand BE.

项目总结/摘要 食管腺癌（EAC）是一个严重的临床问题，由于其发病率迅速上升 率，以及目前有限的治疗选择。这种疾病现在已经超过了其他组织学 食管肿瘤的类型在美国。EAC的主要危险因素是胃食管反流病 （GERD），影响10%至20%的美国人口。在GERD的条件下，食管细胞是前- 使其暴露于混合有十二指肠胆汁盐的酸性胃液。回流会导致慢性炎症， 和过度氧化DNA损伤，导致肿瘤发生改变和进展的积累 通过巴雷特化生（BE）转移到EAC。然而，恶性肿瘤背后的精确分子事件 食管细胞的转化仍然知之甚少，从而限制了对食管癌的靶点的鉴定。 筛查高危患者和开发食管肿瘤的新疗法。 我们提出了一个新的假说来研究食管细胞的致瘤性转化 在食管反流损伤的情况下。这一假设得到了来自人类的强有力的初步数据的支持。 组织、动物模型和广泛的体外研究。我们已经证明，6 Np 73蛋白发挥作用， 通过抑制巴雷特食管中的关键肿瘤抑制蛋白在食管肿瘤发生中发挥关键作用 细胞暴露于慢性胃食管反流。我们还发现了导致 6 Np 73激活。 我们将在这些发现的基础上，进一步研究6 Np 73和其他成员的作用。 p53蛋白家族在食管腺癌发生发展中的作用在目标1中，我们将剖析 6 Np 73在EAC进展过程中上调。在目标2中，我们将研究食管肿瘤的发生， vivo.我们将采用新的胃食管反流损伤小鼠模型和食管器官型培养， 这些方法概括了人类GERD相关的病理学并剖析了6 Np 73的功能。这些研究将 补充人类食管癌前病变和癌性病变的分析。在目标3中，我们 探讨其在胃食管反流致DNA氧化损伤调控中的生物学作用。 我们的发现将对理解与肿瘤相关的多步骤肿瘤发生产生强烈影响。 GERD和BE。重要的是，我们的研究结果有助于揭示食管肿瘤发展的潜在危险因素。 为在高危患者中开发新的化疗方法奠定基础， 格尔登是