Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9951-6. doi: 10.1073/pnas.1016912108. Epub 2011 May 31.
The tyrosine kinase c-Met promotes the formation and malignant progression of multiple cancers. It is well known that c-Met hyperactivation increases tumorigenicity and tumor cell resistance to DNA damaging agents, properties associated with tumor-initiating stem cells. However, a link between c-Met signaling and the formation and/or maintenance of neoplastic stem cells has not been previously identified. Here, we show that c-Met is activated and functional in glioblastoma (GBM) neurospheres enriched for glioblastoma tumor-initiating stem cells and that c-Met expression/function correlates with stem cell marker expression and the neoplastic stem cell phenotype in glioblastoma neurospheres and clinical glioblastoma specimens. c-Met activation was found to induce the expression of reprogramming transcription factors (RFs) known to support embryonic stem cells and induce differentiated cells to form pluripotent stem (iPS) cells, and c-Met activation counteracted the effects of forced differentiation in glioblastoma neurospheres. Expression of the reprogramming transcription factor Nanog by glioblastoma cells is shown to mediate the ability of c-Met to induce the stem cell characteristics of neurosphere formation and neurosphere cell self-renewal. These findings show that c-Met enhances the population of glioblastoma stem cells (GBM SCs) via a mechanism requiring Nanog and potentially other c-Met-responsive reprogramming transcription factors.
酪氨酸激酶 c-Met 促进了多种癌症的形成和恶性进展。众所周知，c-Met 的过度激活会增加肿瘤的发生和肿瘤细胞对 DNA 损伤剂的耐药性，这些特性与肿瘤起始干细胞有关。然而，c-Met 信号与肿瘤起始干细胞的形成和/或维持之间的联系尚未被确定。在这里，我们表明，c-Met 在富含胶质母细胞瘤起始干细胞的神经球中被激活并发挥功能，并且 c-Met 的表达/功能与神经球中的干细胞标志物表达以及神经球和临床胶质母细胞瘤标本中的肿瘤起始干细胞表型相关。发现 c-Met 的激活诱导了重编程转录因子（RFs）的表达，这些转录因子已知支持胚胎干细胞并诱导分化细胞形成多能干细胞（iPS 细胞），并且 c-Met 的激活拮抗了胶质母细胞瘤神经球中强制分化的作用。胶质母细胞瘤细胞中重编程转录因子 Nanog 的表达介导了 c-Met 诱导神经球形成和神经球细胞自我更新的干细胞特征的能力。这些发现表明，c-Met 通过一种需要 Nanog 及其他潜在的 c-Met 反应性重编程转录因子的机制增强了胶质母细胞瘤干细胞（GBM SCs）的群体。
