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C-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype

机译:C-Met信号传导诱导重编程网络并支持胶质母细胞瘤茎样表型

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摘要

The tyrosine kinase c-Met promotes the formation and malignant progression of multiple cancers. It is well known that c-Met hyper activation 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 em bryonic stem cells and induce differentiated cells to form pluripo tent 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 popula tion of glioblastoma stem cells (GBM SCs) via a mechanism requiring Nanog and potentially other c-Met-responsive reprogramming transcription factors.
机译:酪氨酸激酶c-Met促进多种癌症的形成和恶性进展。众所周知,c-Met的过度活化增加了致癌性和肿瘤细胞对DNA破坏剂的抗性,而DNA破坏剂是与肿瘤引发的干细胞有关的特性。然而,先前尚未发现c-Met信号传导与肿瘤干细胞的形成和/或维持之间的联系。在这里,我们显示c-Met在胶质母细胞瘤(GBM)神经球中被激活并发挥功能,而胶质母细胞瘤肿瘤引发的干细胞富集,并且c-Met的表达/功能与胶质母细胞瘤神经球中的干细胞标志物表达和肿瘤性干细胞表型相关。胶质母细胞瘤标本。发现c-Met激活诱导已知支持胚胎干细胞的重编程转录因子(RFs)的表达,并诱导分化细胞形成多能干细胞(iPS),c-Met激活抵消了强迫分化的作用。胶质母细胞瘤神经球。胶质母细胞瘤细胞表达重编程转录因子Nanog被证明可介导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通过需要Nanog和可能其他c-Met响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 SC)的种群。

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  • 作者单位

    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205,Departments of Neurology;

    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205;

    Institute of Reconstructive Neurobiology,Division of ClinicalNeurooncology, Department of Neurology, University of Bonn Medical Center, D-53105 Bonn, Germany;

    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205,Departments of Neurology;

    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205,Departments of Neurology;

    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205;

    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205,Departments of Neurology;

    Institute of Reconstructive Neurobiology;

    Neurosurgery;

    Pathology;

    Neurosurgery,Oncology, and;

    Institute of Reconstructive Neurobiology;

    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205,Departments of Neurology,Oncology, and ,Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21287;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cancer stem cell; hepatocyte growth factor; sox2; oct4; klf4;

    机译:癌症干细胞;肝细胞生长因子;sox2;oct4;klf4;

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