Wnt and BMP signals control intestinal adenoma cell fates
Wnt and BMP signals control intestinal adenoma cell fates
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DOI：
10.1002/ijc.27500
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发表时间：
2012-11-15
影响因子：
6.4
通讯作者：
Morkel, Markus
中科院分区：
文献类型：
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作者：
Farrall, Alexandra L.;Riemer, Pamela;Morkel, Markus
控制肠腺瘤细胞的干性和分化的细胞层次和信号尚不清楚。在这项研究中，我们使用器官型培养来研究β-连环蛋白和BMP信号在小鼠肠腺瘤形成细胞中的影响。我们发现，APC缺失或致癌突变β-连环蛋白（Ctnnb 1 mut）的转基因诱导激活β-连环蛋白信号传导启动未转化的肠细胞向肿瘤细胞的转化。这些肿瘤细胞显示出癌症干细胞（CSC）特性，例如CSC标志物Cd 133和Cd 44的表达增加，自我更新的高能力和无限的增殖潜力。转基因Ctnnb 1 mut的后续失活导致肿瘤细胞逆转为正常肠干细胞，其立即重新安装正常肠上皮的细胞层级。我们的数据表明，β-连环蛋白信号的致癌激活在不可逆的遗传或表观遗传变化的情况下启动肠细胞转化的早期步骤。有趣的是，我们发现培养物和腺瘤中的肿瘤细胞产生BMP 4，其通过启动不可逆的细胞分化和自我更新能力的丧失来抵消CSC样特征。我们的结论是，反对干维持致癌β-连环蛋白信号和自分泌分化的BMP信号在腺瘤细胞内提供了一个合理的形成细胞层次结构在肠腺瘤，并可能有助于限制腺瘤的生长。
Cellular hierarchies and signals that govern stemness and differentiation of intestinal adenoma cells are not well defined. In this study, we used organotypic culture to investigate the impact of beta-catenin and BMP signals in cells that form intestinal adenoma in the mouse. We found that activation of beta-catenin signaling by loss of APC or transgenic induction of oncogenic mutant beta-catenin (Ctnnb1mut) initiates the conversion of untransformed intestinal cells to tumor cells. These tumor cells display cancer stem cell (CSC) traits such as increased expression of the CSC markers Cd133 and Cd44, a high capacity for self-renewal and unlimited proliferative potential. Subsequent inactivation of transgenic Ctnnb1mut results in the reversion of tumor cells to normal intestinal stem cells, which immediately reinstall the cellular hierarchy of the normal intestinal epithelium. Our data demonstrate that oncogenic activation of beta-catenin signaling initiates the early steps of intestinal cellular transformation in the absence of irreversible genetic or epigenetic changes. Interestingly, we found that tumor cells in culture and in adenoma produce BMP4, which counteracts CSC-like traits by initiating irreversible cellular differentiation and loss of self-renewal capacity. We conclude that the opposition of stemness-maintaining oncogenic beta-catenin signals and autocrine differentiating BMP signals within the adenoma cell provides a rationale for the formation of cellular hierarchies in intestinal adenoma and may serve to limit adenoma growth.