Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals.
Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals.
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DOI：
10.1093/jb/mvt112
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发表时间：
2014-04
影响因子：
2.7
通讯作者：
D. Yamada;Takayuki Hoshii;Shingo Tanaka;A. Hegazy;Masahiko Kobayashi;Y. Tadokoro;Kumiko Ohta;M. Ueno;Mohamed A. E. Ali;A. Hirao
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文献类型：
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作者：
D. Yamada;Takayuki Hoshii;Shingo Tanaka;A. Hegazy;Masahiko Kobayashi;Y. Tadokoro;Kumiko Ohta;M. Ueno;Mohamed A. E. Ali;A. Hirao
胶质母细胞瘤经常具有刺激哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）活性的遗传病变。结节性硬化症复合体1（TSC 1）或TSC 2的杂合性缺失，共同形成mTORC 1的关键负调节因子，也见于胶质母细胞瘤;然而，尚不清楚TSC复合体的缺失如何影响恶性胶质瘤的发展。在这里，我们研究了Tsc 1在小鼠胶质瘤发生中的作用。Tsc 1缺陷上调mTORC 1活性，并抑制神经干/祖细胞（NSPCs）在一系列的神经球形成试验的增殖，表明Tsc 1缺陷的NSPCs有缺陷的自我更新活性。Tsc 1缺陷的NSPCs的神经球形成能力通过p16（Ink 4a）p19（Arf）缺陷而恢复。联合Tsc 1和p16（Ink 4a）p19（Arf）缺陷在NSPCs中不会引起体内胶质瘤的发生。然而，在由表皮生长因子受体（EGFR）的活性突变体EGFRvIII驱动的胶质瘤模型中，Tsc 1的缺失导致胶质瘤发展的早期发作。Tsc 1缺失导致的mTORC 1过度激活加速了恶性表型，包括肿瘤质量增加和微血管形成增强，导致颅内出血。这些数据表明，虽然mTORC 1过度活化本身可能不足以促进胶质瘤的发生，但当与致癌信号结合时，它是胶质瘤发展的有效修饰剂。
Glioblastomas frequently harbour genetic lesions that stimulate the activity of mammalian target of rapamycin complex 1 (mTORC1). Loss of heterozygosity of tuberous sclerosis complex 1 (TSC1) or TSC2, which together form a critical negative regulator of mTORC1, is also seen in glioblastoma; however, it is not known how loss of the TSC complex affects the development of malignant gliomas. Here we investigated the role of Tsc1 in gliomagenesis in mice. Tsc1 deficiency up-regulated mTORC1 activity and suppressed the proliferation of neural stem/progenitor cells (NSPCs) in a serial neurosphere-forming assay, suggesting that Tsc1-deficient NSPCs have defective self-renewal activity. The neurosphere-forming capacity of Tsc1-deficient NSPCs was restored by p16(Ink4a)p19(Arf) deficiency. Combined Tsc1 and p16(Ink4a)p19(Arf) deficiency in NSPCs did not cause gliomagenesis in vivo. However, in a glioma model driven by an active mutant of epidermal growth factor receptor (EGFR), EGFRvIII, loss of Tsc1 resulted in an earlier onset of glioma development. The mTORC1 hyperactivation by Tsc1 deletion accelerated malignant phenotypes, including increased tumour mass and enhanced microvascular formation, leading to intracranial haemorrhage. These data demonstrate that, although mTORC1 hyperactivation itself may not be sufficient for gliomagenesis, it is a potent modifier of glioma development when combined with oncogenic signals.