Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling
Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling
复制标题
癌症相关成纤维细胞通过旁分泌信号调节肺癌干细胞的可塑性
DOI：
10.1038/ncomms4472
复制
发表时间：
2014-03-01
影响因子：
16.6
通讯作者：
Yang, Pan-Chyr
中科院分区：
文献类型：
--
作者：
Chen, Wan-Jiun;Ho, Chao-Chi;Yang, Pan-Chyr
癌症干细胞（Cancer stem cells, CSCs）是治疗癌症的一个很有前景的靶点，但在体内如何维持CSC的可塑性尚不清楚，并且很难在体外研究。在这里，我们建立了一个可持续的原代培养，用CD90（+）癌症相关成纤维细胞（CAFs）喂养Oct3/4(+)/Nanog（+）肺CSCs，以进一步提高我们在肿瘤微环境中保存干细胞的知识。利用转录组学，我们确定了caf通过去分化和重新获得干细胞样特性来富集CSCs的旁分泌网络。具体来说，我们发现在表达IGF-II的cas存在的情况下，癌细胞中的IGF1R信号激活可以诱导Nanog的表达并促进其干细胞性。此外，这种旁分泌信号可以预测I期非小细胞肺癌（NSCLC）患者的总生存率和无复发生存率。IGF-II/ IGF1R信号阻断抑制Nanog表达并减弱癌症干细胞特征。我们的数据表明，caf构成了癌症干细胞的支持利基，靶向这种旁分泌信号可能为非小细胞肺癌提供一种新的治疗策略。
Cancer stem cells (CSCs) are a promising target for treating cancer, yet how CSC plasticity is maintained in vivo is unclear and is difficult to study in vitro. Here we establish a sustainable primary culture of Oct3/4(+)/Nanog(+) lung CSCs fed with CD90(+) cancer-associated fibroblasts (CAFs) to further advance our knowledge of preserving stem cells in the tumour microenvironment. Using transcriptomics we identify the paracrine network by which CAFs enrich CSCs through de-differentiation and reacquisition of stem cell-like properties. Specifically, we find that IGF1R signalling activation in cancer cells in the presence of CAFs expressing IGF-II can induce Nanog expression and promote stemness. Moreover, this paracrine signalling predicts overall and relapse-free survival in stage I non-small cell lung cancer (NSCLC) patients. IGF-II/ IGF1R signalling blockade inhibits Nanog expression and attenuates cancer stem cell features. Our data demonstrate that CAFs constitute a supporting niche for cancer stemness, and targeting this paracrine signalling may present a new therapeutic strategy for NSCLC.