Stem cell signature in glioblastoma: therapeutic development for a moving target
Stem cell signature in glioblastoma: therapeutic development for a moving target
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DOI：
10.3171/2014.9.jns132253
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发表时间：
2015-02-01
影响因子：
4.1
通讯作者：
Nakano, Ichiro
中科院分区：
文献类型：
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作者：
Nakano, Ichiro
成人高级别胶质瘤（HGG）的肿瘤异质性基于核心基因特征被识别为3个主要亚型。然而，胶质瘤干细胞（GSCs）在单个HGG亚型中的分子特征和临床意义仍然缺乏表征。最近，全基因组转录分析确定了两种相互排斥的GSC亚型，它们具有不同的信号和代谢途径失调。遗传谱分析和表型分析区分了原膜（PN）和间充质（MES） GSCs，并揭示了与相应的PN或MES hgg的显著相关性。与具有MES特征的hgg相似，MES GSCs在体外和体内都表现出更具侵略性的表型。此外，MES GSCs与PN GSCs相比具有明显的耐辐射性，这与MES GBM与其他亚型相比的相对耐辐射性一致。系统生物学方法已经确定了一组转录因子作为MES特征的主调控因子。在MES GSCs中，代谢重编程也被注意到，包括醛脱氢酶（ALDH）家族基因在内的糖酵解途径被显著激活。本文综述了近年来HGG和GSC不同亚型的分子特征表征、不同GSC亚型之间以及GSC和非GSC之间在HGG肿瘤中的可塑性的研究进展。本文还讨论了转译GSC研究的临床意义。
Tumor heterogeneity of adult high-grade glioma (HGG) is recognized in 3 major subtypes based on core gene signatures. However, the molecular signatures and clinical implications of glioma stem cells (GSCs) in individual HGG subtypes remain poorly characterized. Recently genome-wide transcriptional analysis identified two mutually exclusive GSC subtypes with distinct dysregulated signaling and metabolic pathways. Analysis of genetic profiles and phenotypic assays distinguished proneural (PN) from mesenchymal (MES) GSCs and revealed a striking correlation with the corresponding PN or MES HGGs. Similar to HGGs with a MES signature, MES GSCs display more aggressive phenotypes both in vitro and in vivo. Furthermore, MES GSCs are markedly resistant to radiation as compared with PN GSCs, consistent with the relative radiation resistance of MES GBM compared with other subtypes. A systems biology approach has identified a set of transcription factors as the master regulators for the MES signature. Metabolic-reprogramming in MES GSCs has also been noticed with the prominent activation of the glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes. This review summarizes recent progress in the characterization of the molecular signature in distinct HGG and GSC subtypes and plasticity between different GSC subtypes as well as between GSCs and non-GSCs in HGG tumors. Clinical implications of the translational GSC research are also discussed.