Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
Neuro Oncol. 2010 Dec;12(12):1205-19. doi: 10.1093/neuonc/noq103. Epub 2010 Sep 22.
Glioblastoma, the most intractable cerebral tumor, is highly lethal. Recent studies suggest that cancer stem-like cells (CSLCs) have the capacity to repopulate tumors and mediate radio- and chemoresistance, implying that future therapies may need to turn from the elimination of rapidly dividing, but differentiated, tumor cells to specifically targeting the minority of tumor cells that repopulate the tumor. However, the mechanism by which glioblastoma CSLCs maintain their immature stem-like state or, alternatively, become committed to differentiation is poorly understood. Here, we show that the inactivation of mammalian target of rapamycin (mTor) by the mTor inhibitor rapamycin or knockdown of mTor reduced sphere formation and the expression of neural stem cell (NSC)/progenitor markers in CSLCs of the A172 glioblastoma cell line. Interestingly, combination treatment with rapamycin and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, not only reduced the expression of NSC/progenitor markers more efficiently than single-agent treatment, but also increased the expression of βIII-tubulin, a neuronal differentiation marker. Consistent with these results, a dual PI3K/mTor inhibitor, NVP-BEZ235, elicited a prodifferentiation effect on A172 CSLCs. Moreover, A172 CSLCs, which were induced to undergo differentiation by pretreatment with NVP-BEZ235, exhibited a significant decrease in their tumorigenicity when transplanted either subcutaneously or intracranially. Importantly, similar results were obtained when patient-derived glioblastoma CSLCs were used. These findings suggest that the PI3K/mTor signaling pathway is critical for the maintenance of glioblastoma CSLC properties, and targeting both mTor and PI3K of CSLCs may be an effective therapeutic strategy in glioblastoma.
胶质母细胞瘤是最棘手的脑肿瘤，具有高度致命性。最近的研究表明，癌症干细胞样细胞（CSLCs）具有重新填充肿瘤并介导放射和化学抗性的能力，这意味着未来的治疗方法可能需要从消除快速分裂但分化的肿瘤细胞转向专门针对重新填充肿瘤的少数肿瘤细胞。然而，胶质母细胞瘤 CSLC 维持其不成熟的干细胞样状态或选择分化的机制尚不清楚。在这里，我们表明，雷帕霉素或 mTor 敲低通过哺乳动物雷帕霉素靶蛋白（mTor）抑制剂雷帕霉素使 mTor 失活，减少了 A172 胶质母细胞瘤细胞系 CSLC 的球体形成和神经干细胞/祖细胞标志物的表达。有趣的是，雷帕霉素与磷脂酰肌醇 3-激酶（PI3K）抑制剂 LY294002 的联合治疗不仅比单一药物治疗更有效地降低 NSC/祖细胞标志物的表达，而且还增加了神经元分化标志物 βIII-微管蛋白的表达。与这些结果一致，双重 PI3K/mTor 抑制剂 NVP-BEZ235 对 A172 CSLC 产生促分化作用。此外，用 NVP-BEZ235 预处理诱导分化的 A172 CSLCs 在皮下或颅内移植时其致瘤性显著降低。重要的是，当使用患者来源的胶质母细胞瘤 CSLCs 时，获得了类似的结果。这些发现表明，PI3K/mTor 信号通路对于维持胶质母细胞瘤 CSLC 特性至关重要，靶向 CSLC 的 mTor 和 PI3K 可能是胶质母细胞瘤的有效治疗策略。
