Department of Neurosurgery, Graduate School of Comprehensive Human Sciences, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Stem Cells. 2013 Apr;31(4):627-40. doi: 10.1002/stem.1328.
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.
癌症干细胞（CSCs）由于其内在特性，如高 DNA 修复能力和抗氧化能力，在放射治疗后疾病复发中起着重要作用。然而，CSCs 如何进一步适应以逃避临床实践中反复放射治疗方案的毒性尚不清楚。在这里，我们使一群鼠脑胶质瘤干细胞（GSCs）暴露于分次放射中，以研究相关的适应性变化，最终目的是确定可调节获得性放射抗性的靶因子。我们已经表明，分次照射诱导 IGF1 分泌增加和 IGF 型 1 受体（IGF1R）在 GSCs 中的逐渐上调。有趣的是，IGF1R 上调发挥双重放射保护作用。在静止状态下，持续的 IGF1 刺激最终导致 Akt/细胞外信号调节激酶（ERK）的下调和 FoxO3a 的激活，导致增殖速度减慢和自我更新增强。相比之下，在急性照射后，IGF1R 的丰度增加和 IGF1 的分泌增加促进了从潜伏状态向 Akt 存活信号激活的快速转变，从而保护 GSCs 免受放射毒性。用 IGF1R 抑制剂治疗具有放射抗性的 GSCs 形成的肿瘤导致放射敏感性显著增加，表明阻断 IGF1R 信号是逆转放射抗性的有效策略。总之，我们的研究结果表明，GSCs 不仅通过内在特性，而且通过逐渐诱导抵抗途径来逃避重复放射的损伤，并确定 IGF1R 信号对 GSCs 的动态调节是适应性放射保护的一种新机制。
