IGF1 Receptor Signaling Regulates Adaptive Radioprotection in Glioma Stem Cells
IGF1 Receptor Signaling Regulates Adaptive Radioprotection in Glioma Stem Cells
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DOI：
10.1002/stem.1328
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发表时间：
2013-04-01
期刊：
影响因子：
5.2
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
--
作者：
Osuka, Satoru;Sampetrean, Oltea;Saya, Hideyuki
肿瘤干细胞（cancer stem cells，CSCs）具有高度的DNA修复能力和抗氧化能力，在肿瘤放疗后的复发中发挥重要作用。然而，目前尚不清楚CSC如何进一步适应以逃避临床实践中使用的重复照射方案的毒性。在这里，我们已经暴露了一群鼠胶质瘤干细胞（GSC）的分级辐射，以调查相关的适应性变化，最终目标是确定一个可靶向的因素，调节获得性辐射抗性。我们已经表明，分次辐射诱导GSC中IGF 1分泌的增加和IGF 1型受体（IGF 1 R）的逐渐上调。有趣的是，IGF 1 R上调发挥双重辐射防护作用。在静息状态下，持续的IGF 1刺激最终诱导Akt/细胞外信号调节激酶（ERK）和FoxO 3a激活的下调，这导致增殖较慢和自我更新增强。相反，在急性辐射后，IGF 1 R的丰度和IGF 1分泌的增加促进从潜伏状态向Akt存活信号传导的激活的快速转变，保护GSC免受辐射毒性。用IGF 1 R抑制剂治疗由辐射抗性GSC形成的肿瘤导致辐射敏感性显著增加，表明IGF 1 R信号传导的阻断是逆转辐射抗性的有效策略。总之，我们的研究结果表明，GSCs逃避重复辐射的损害，不仅通过先天的属性，而且通过逐步诱导的阻力途径，并确定GSCs的动态调节IGF 1 R信号作为一种新的适应性辐射防护机制。干细胞2013;31：627640
Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection. STEM CELLS 2013;31:627640