MECHANISMS OF ADAPTIVE RADIOPROTECTION IN GLIOMA STEM CELLS

Abstract

BACKGROUND: Cancer stem cells (CSCs) play an important role in disease recurrence. Intrinsic characteristics such as high DNA repair ability and quiescence allow CSCs to survive acute injury. It is unclear, however, how CSCs escape the toxicity of the long-term treatment regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation and investigated the associated adaptive changes and their molecular determinants. METHODS: Initial tumors were formed by implantation of Ink4a/Arf-null neural stem cells overexpressing H-RASV12 into the forebrain of wild-type mice. GSCs purified from these tumors were then grown as tumorspheres and subjected to 60Gy of fractionated radiation. Control and post-irradiation GSCs and their allografts were compared to identify differentially expressed factors that underlie acquired radioresistance. RESULTS: Analysis of the molecular changes induced in GSCs during fractionated radiation revealed an increase in IGF1 secretion and a gradual up-regulation of the IGF type 1 receptor (IGF1R). Interestingly, IGF1-IGF1R up-regulation exerted a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induced down-regulation of Akt/ERK and FoxO3a activation, which resulted in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promoted a rapid shift from a latent state towards activation of Akt survival signaling, protecting GSCs from radiation toxicity. Moreover, the IGF1 secretion could also exert protective effects in a paracrine manner, further enhancing overall radioresistance. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity. CONCLUSIONS: Our results show that GSCs can evade the damage of repeated radiation not only through innate properties, but also by establishing an IGF1-IGF1R autocrine trophic loop. Elucidation of stem-cell-specific mechanisms of adaptive resistance and identification of targetable key factors are crucial to the refinement of current treatment strategies and prevention of tumor relapse. SECONDARY CATEGORY: n/a.