Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance.
Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance.
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DOI：
10.1038/cddis.2014.509
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发表时间：
2014-11-27
影响因子：
9
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胶质母细胞瘤(GBM)是一种预后较差的脑肿瘤，尽管传统的治疗方法是手术切除和随后的放化疗。在这些异质肿瘤中，耐化疗和抗放射的GBM干细胞亚群似乎与系统性的GBM复发有关。此外，最近的研究表明，分化的肿瘤细胞可能具有去分化的能力，并获得干细胞样的表型，这种现象也称为可塑性，以响应微环境压力，如缺氧。我们假设GBM细胞在电离辐射(IRS)后可能经历类似的去分化过程，从而支持GBM在放射治疗后快速复发。在目前的研究中，我们证明了从患者切除的分化的GBM细胞的亚毒性IR暴露增强了干细胞相关属性的长期重新获得，如产生初级和次级神经球的能力，干性标记的表达和增加的致瘤性。在这个过程中，我们还发现了抗凋亡蛋白Survivin的上调，我们发现它的特异性下调导致了IR诱导的可塑性的阻断。综上所述，这些结果表明，辐射可以通过Survivin依赖的途径调节GBM细胞的去分化。针对与IR诱导的可塑性相关的机制，可能有助于开发一些创新的药理学策略，以改善这些侵袭性脑癌的放射增敏。
Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.