Hedgehog Signaling Regulates Brain Tumor-Initiating Cell Proliferation and Portends Shorter Survival for Patients with PTEN-Coexpressing Glioblastomas
Hedgehog Signaling Regulates Brain Tumor-Initiating Cell Proliferation and Portends Shorter Survival for Patients with PTEN-Coexpressing Glioblastomas
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DOI：
10.1634/stemcells.2008-0459
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发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
Yu, John S.
中科院分区：
文献类型：
--
作者：
Xu, Qijin;Yuan, Xiangpeng;Yu, John S.
脑肿瘤干细胞(BTSCs)的鉴定揭示了生物自我更新机制在临床脑肿瘤发生和增殖中的作用。然而，BTSCs成瘤能力的分子机制仍不清楚。在这里，我们利用BTSCs的基因表达谱生成了多形性胶质母细胞瘤(GBM)的分子特征，并鉴定了Sonic Hedgehog(SHH)信号依赖和独立的BTSCs及其各自的胶质母细胞瘤手术标本。在体外和无瘤小鼠的颅内肿瘤模型中，BTSC的增殖可以以一种途径依赖的方式被抑制。SHH依赖和非SHH依赖的脑瘤生长都需要肌醇磷脂3-激酶-哺乳动物雷帕霉素信号的靶点。在人肾小球基底膜中，PTEN表达肿瘤的SHH和ptch1表达水平显著高于PTEN缺陷肿瘤。此外，我们还发现，在PTEN共表达人GBM中，过度活跃的SHH-GLI信号与存活时间的减少有关。因此，不同的增殖信号依赖可能支持BTSCs的胶质母细胞瘤生长。模拟这些BTSC的增殖机制可能会为个体化治疗胶质母细胞瘤提供理论基础。干细胞2008；26：3018-3026
The identification of brain tumor stem-like cells (BTSCs) has implicated a role of biological self-renewal mechanisms in clinical brain tumor initiation and propagation. The molecular mechanisms underlying the tumor-forming capacity of BTSCs, however, remain unknown. Here, we have generated molecular signatures of glioblastoma multiforme (GBM) using gene expression profiles of BTSCs and have identified both Sonic Hedgehog (SHH) signaling-dependent and -independent BTSCs and their respective glioblastoma surgical specimens. BTSC proliferation could be abrogated in a pathway-dependent fashion in vitro and in an intracranial tumor model in athymic mice. Both SHH-dependent and -independent brain tumor growth required phosphoinositide 3-kinase-mammalian target of rapamycin signaling. In human GBMs, the levels of SHH and PTCH1 expression were significantly higher in PTEN-expressing tumors than in PTEN-deficient tumors. In addition, we show that hyperactive SHH-GLI signaling in PTEN-coexpressing human GBM is associated with reduced survival time. Thus, distinct proliferation signaling dependence may underpin glioblastoma propagation by BTSCs. Modeling these BTSC proliferation mechanisms may provide a rationale for individualized glioblastoma treatment. STEM CELLS 2008; 26: 3018-3026