Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells
Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells
复制标题
DOI：
10.1038/nature03659
复制
发表时间：
2005-06-16
期刊：
影响因子：
64.8
通讯作者：
Clevers, H
中科院分区：
文献类型：
--
作者：
van Es, JH;van Gijn, ME;Clevers, H
小肠的自我更新上皮有序地分为干/祖细胞隐窝室和分化的绒毛室。最近的证据表明，Wnt级联是控制细胞命运沿着隐窝-绒毛轴的主导力量（1）。在这里，我们展示了在有条件去除常见的Notch途径转录因子CSL/RBP-J后，增殖的隐窝细胞快速、大量地转化为有丝分裂后的杯状细胞（参考文献2）。我们通过用γ-分泌酶抑制剂阻断Notch级联反应获得了相似的表型。该抑制剂还诱导携带Apc肿瘤抑制基因突变的小鼠腺瘤中的杯状细胞分化。因此，在隐窝和腺瘤中维持未分化的增殖细胞需要Notch和Wnt级联的协同激活。我们的数据表明，γ-分泌酶抑制剂，开发阿尔茨海默氏症，可能是治疗大肠肿瘤性疾病的好处。
The self-renewing epithelium of the small intestine is ordered into stem/progenitor crypt compartments and differentiated villus compartments. Recent evidence indicates that the Wnt cascade is the dominant force in controlling cell fate along the crypt-villus axis(1). Here we show a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J (ref. 2). We obtained a similar phenotype by blocking the Notch cascade with a gamma-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumour suppressor gene. Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. Our data indicate that gamma-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.