胆汁酸和炎症激活了巴雷特样化生小鼠模型中的胃贲门干细胞。
Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.
机构信息
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
出版信息
Cancer Cell. 2012 Jan 17;21(1):36-51. doi: 10.1016/j.ccr.2011.12.004.
Abstract
Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5(+) gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling.
摘要
食管腺癌（EAC）源自 Barrett 食管（BE），后者与反流性食管炎相关，表现为肠上皮样柱状化生。在 BE 的转基因小鼠模型中，IL-1β在食管中的过表达可模拟人类病理，导致食管炎、Barrett 样化生和 EAC 的演变。组织病理学和基因特征与人类 BE 非常相似，表现为 TFF2、Bmp4、Cdx2、Notch1 和 IL-6 的上调。胆汁酸和/或亚硝胺的暴露会加速 BE 和 EAC 的发展，而 IL-6 缺乏则会抑制其发展。存在于 BE 中的 Lgr5(+)胃贲门干细胞能够对早期 BE 病变进行谱系追踪。我们的数据表明，BE 和 EAC 源自胃祖细胞，这归因于促进肿瘤生长的 IL-1β-IL-6 信号级联和 Dll1 依赖性 Notch 信号。
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