Abstract 238: IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells.

Abstract

Abstract Background: Cancer stem cells play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as quiescence and high DNA repair capability. It is unclear, however, how cancer stem cells 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. Methods: Initial tumors were formed by implantation of Ink4a/Arf -/- neural stem cells overexpressing H-RASV12 into the forebrain of wild-type mice. GSCs purified from the tumors were then grown as tumorspheres (TS), with a subgroup, TS-RR, surviving repeated radiation (12x 5Gy). The two types of cells, their subclones and allografts were compared to identify differentially expressed factors that underlie acquired radioresistance. Results: TS-RR were more resistant than TS to further radiation, both in vitro and in vivo. Analysis of the subclones showed that even the most resistant TS subclones did not reach the radioresistance level of TS-RR, suggesting that TS-RR may have acquired radioresistance de novo during the repeated irradiation. Analysis of the molecular changes induced in TS during fractionated radiation revealed an increase in IGF1 secretion and a gradual up-regulation of the IGF type 1 receptor (IGF1R). Interestingly, 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. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity. Conclusion: 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, which results in acquired resistance to radiation. Elucidation of stem-cell-specific adaptive radioprotection mechanisms and identification of targetable key factors are crucial to the refinement of radiosensitizing strategies and prevention of tumor relapse. Citation Format: Satoru Osuka, Oltea Sampetrean, Takatsune Shimizu, Isako Saga, Nobuyuki Onishi, Eiji Sugihara, Jun Okubo, Satoshi Fujita, Shingo Takano, Akira Matsumura, Hideyuki Saya. IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 238. doi:10.1158/1538-7445.AM2013-238