Wnt activity defines colon cancer stem cells and is regulated by the microenvironment
Wnt activity defines colon cancer stem cells and is regulated by the microenvironment
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DOI：
10.1038/ncb2048
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发表时间：
2010-05-01
影响因子：
21.3
通讯作者：
Medema, Jan Paul
中科院分区：
文献类型：
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作者：
Vermeulen, Louis;Melo, Felipe De Sousa E.;Medema, Jan Paul
尽管APC或β-连环蛋白中存在突变，据信其组成性地激活Wnt信号级联，但当分析β-连环蛋白定位时，大多数结直肠癌显示细胞异质性，表明Wnt信号的调节更复杂。我们用Wnt报告基因构建体探索了这种异质性，并观察到高Wnt活性在功能上指定了结肠癌干细胞（CSC）群体。在腺癌中，Wnt通路的高活性优先在位于接近基质肌成纤维细胞的肿瘤细胞中观察到，表明Wnt活性和癌症干性可能受外在因素调节。与此观点一致，肌成纤维细胞分泌的因子，特别是肝细胞生长因子，激活β-连环蛋白依赖性转录，随后激活CSC克隆形成。更重要的是，成肌纤维细胞分泌的因子还在体外和体内恢复更分化的肿瘤细胞中的CSC表型。因此，我们提出结肠癌细胞的干性部分是由微环境精心策划的，并且是一种比先前预期的更动态的质量，可以通过高Wnt活性来定义。
Despite the presence of mutations in APC or beta-catenin, which are believed to activate the Wnt signalling cascade constitutively, most colorectal cancers show cellular heterogeneity when beta-catenin localization is analysed, indicating a more complex regulation of Wnt signalling. We explored this heterogeneity with a Wnt reporter construct and observed that high Wnt activity functionally designates the colon cancer stem cell (CSC) population. In adenocarcinomas, high activity of the Wnt pathway is observed preferentially in tumour cells located close to stromal myofibroblasts, indicating that Wnt activity and cancer stemness may be regulated by extrinsic cues. In agreement with this notion, myofibroblast-secreted factors, specifically hepatocyte growth factor, activate beta-catenin-dependent transcription and subsequently CSC clonogenicity. More significantly, myofibroblast-secreted factors also restore the CSC phenotype in more differentiated tumour cells both in vitro and in vivo. We therefore propose that stemness of colon cancer cells is in part orchestrated by the microenvironment and is a much more dynamic quality than previously expected that can be defined by high Wnt activity.