TGF-β is an inducer of ZEB1-dependent mesenchymal transdifferentiation in glioblastoma that is associated with tumor invasion.
TGF-β is an inducer of ZEB1-dependent mesenchymal transdifferentiation in glioblastoma that is associated with tumor invasion.
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DOI：
10.1038/cddis.2014.395
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发表时间：
2014-10-02
影响因子：
9
通讯作者：
Kruyt FA
中科院分区：
文献类型：
--
作者：
Joseph JV;Conroy S;Tomar T;Eggens-Meijer E;Bhat K;Copray S;Walenkamp AM;Boddeke E;Balasubramanyian V;Wagemakers M;den Dunnen WF;Kruyt FA
胶质母细胞瘤（GBM）的不同分子亚型最近已被确定，其中间充质亚型与最严重的肿瘤相关。在这里，我们报告了转化生长因子-β（TGF-β）能够诱导GBM中的间充质表型，其涉及SMAD 2和ZEB 1的激活，SMAD 2和ZEB 1是上皮癌中间充质转化的已知转录诱导物。在体外和原位小鼠模型中，已建立和新产生的GBM细胞系的TGF-β暴露与形态学变化、增强的间充质标志物表达、迁移和侵袭相关。TGF-β诱导的间充质分化和侵袭行为通过化学抑制TGF-β信号传导以及小干扰RNA（siRNA）依赖性沉默ZEB1来阻止。此外，在体外鉴定了TGF-β反应性和非反应性GBM神经球。有趣的是，无应答细胞已经显示出高水平的pSMAD 2和ZEB 1，其不能通过抑制TGF-β信号传导来抑制，这表明涉及未知的机制。这些不同的GBM神经球在小鼠中形成侵袭性肿瘤，并在免疫组织化学分析中显示间充质标记物表达。此外，我们还在GBM患者材料中检测到具有重叠pSMAD2、升高的ZEB 1和间充质标志物表达的不同区域，这表明诱导了局部微环境依赖性间充质分化。总之，我们的研究结果表明，GBM细胞可以获得与分泌性细胞因子如TGF-β刺激后增强的侵袭潜力相关的间充质特征。GBM的这种特性导致了这种肿瘤类型的异质性，并可能模糊了所提出的转录亚型之间的界限。靶向TGF-β或下游靶点如ZEB1可能在减少患者亚群中GBM的侵袭性表型方面具有潜在益处。
Different molecular subtypes of glioblastoma (GBM) have been recently identified, of which the mesenchymal subtype is associated with worst prognoses. Here, we report that transforming growth factor-β (TGF-β) is able to induce a mesenchymal phenotype in GBM that involves activation of SMAD2 and ZEB1, a known transcriptional inducer of mesenchymal transition in epithelial cancers. TGF-β exposure of established and newly generated GBM cell lines was associated with morphological changes, enhanced mesenchymal marker expression, migration and invasion in vitro and in an orthotopic mouse model. TGF-β-induced mesenchymal differentiation and invasive behavior was prevented by chemical inhibition of TGF-β signaling as well as small interfering RNA (siRNA)-dependent silencing of ZEB1. Furthermore, TGF-β-responding and -nonresponding GBM neurospheres were identified in vitro. Interestingly, nonresponding cells displayed already high levels of pSMAD2 and ZEB1 that could not be suppressed by inhibition of TGF-β signaling, suggesting the involvement of yet unknown mechanisms. These different GBM neurospheres formed invasive tumors in mice as well as revealed mesenchymal marker expression in immunohistochemical analyses. Moreover, we also detected distinct zones with overlapping pSMAD2, elevated ZEB1 and mesenchymal marker expression in GBM patient material, suggestive of the induction of local, microenvironment-dependent mesenchymal differentiation. Overall, our findings indicate that GBM cells can acquire mesenchymal features associated with enhanced invasive potential following stimulation by secretory cytokines, such as TGF-β. This property of GBM contributes to heterogeneity in this tumor type and may blur the boundaries between the proposed transcriptional subtypes. Targeting TGF-β or downstream targets like ZEB1 might be of potential benefit in reducing the invasive phenotype of GBM in a subpopulation of patients.