Conversion of metaplastic Barrett's epithelium into post-mitotic goblet cells by γ-secretase inhibition
Conversion of metaplastic Barrett's epithelium into post-mitotic goblet cells by γ-secretase inhibition
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DOI：
10.1242/dmm.003012
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发表时间：
2010-01-01
影响因子：
4.3
通讯作者：
Clevers, Hans
中科院分区：
文献类型：
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作者：
Menke, Vivianda;van Es, Johan H.;Clevers, Hans
Barrett食管（BE）影响大约2%的西方人群，每年有0.5%的患者进展为食管腺癌（EAC）。在BE中，由于慢性胃十二指肠反流，复层上皮被膀胱型上皮取代。由于肠隐窝的自我更新是由Notch信号驱动的，我们研究了该途径是否在BE的增殖隐窝中是活跃的。免疫组织化学证实了在化生BE上皮中存在完整和活化的Notch信号传导途径，但在正常人食管中不存在。在两种众所周知的人巴雷特衍生的EAC细胞系OE 33和SKGT-5中进行了类似的观察。然后，我们试图研究通过在经充分验证的啮齿动物BE模型中使用γ-分泌酶抑制剂全身治疗的Notch抑制作用。正如我们先前在正常肠上皮中所示，Notch抑制将增殖的Barrett上皮细胞转化为终末分化的杯状细胞，而鳞状上皮保持完整。这些数据表明，局部应用γ-分泌酶抑制剂可能是一种简单的治疗策略，这种日益常见的癌前病变。
Barrett's esophagus (BE) affects approximately 2% of the Western population and progresses to esophageal adenocarcinoma (EAC) in 0 5% of these patients each year. In BE, the stratified epithelium is replaced by an intestinal-type epithelium owing to chronic gastroduodenal reflux. Since self-renewal of intestinal crypts is driven by Notch signaling, we investigated whether this pathway was active in the proliferative crypts of BE. Immunohistochemistry confirmed the presence of an intact and activated Notch signaling pathway in metaplastic BE epithelium, but not in the normal human esophagus Similar observations were made in two well-known human Barrett's-derived EAC cell lines, OE33 and SKGT-5. We then sought to investigate the effects of Notch inhibition by systemic treatment with a gamma-secretase inhibitor in a well-validated rodent model for BE. As we have shown previously in normal intestinal epithelium, Notch inhibition converted the proliferative Barrett's epithelial cells into terminally differentiated goblet cells, whereas the squamous epithelium remained intact. These data imply that local application of gamma-secretase inhibitors may present a simple therapeutic strategy for this increasingly common pre-malignant condition.