Abstract 4171: Preferential radioresistance of glioblastoma stem-like tumor cells that migrate to the olfactory bulb

Abstract

Abstract Brain tumor xenografts initiated from human glioblastoma (GBM) stem-like cells (GSCs) simulate many of the characteristics of GBMs in situ including extensive invasiveness and migration. Using a GSC orthotopic brain tumor model, we tested the hypothesis that location within the brain microenvironment influences the radiosensitivity of GBM cells. At 35 days after implantation of CD133+ NSC11 GSCs into the right striatum of nude mice, tumor cells are detectable throughout the striatum, the corpus callosum and the olfactory bulb. To evaluate radioresponse of tumor cells in each brain region, mice were injected with the halogenated thymidine analog CldU (5-chloro-2'-deoxyuridine), which is incorporated into DNA during S-phase and allows for the identification of proliferating cells. Specifically, NSC11 brain tumor xenografts received a single dose of 10Gy, which results in an approximate 13-day survival advantage, followed by 3 daily intraperitoneal (IP) injections of CldU initiated every 4 days following irradiation. Subsequent immunohistochemical analyses of CldU incorporation along with the GSC marker SOX2 was then used to determine the percentage of proliferating tumor cells in the corpus callosum, striatum, and olfactory bulb. When CldU injections were initiated 4 days post-10Gy, 4% of tumor cells in the corpus callosum, 0.75% in the striatum, and 35% in the olfactory bulb were CldU positive. These values can be compared to 55%, 53%, and 56% CldU positive tumor cells in the corpus callosum, striatum, and olfactory bulb, respectively, of the sham irradiated tumors. These data indicate that by 4 days after irradiation significantly more tumor cells in the olfactory bulb were proliferating than in the corpus callosum or striatum. CldU injections initiated 12 days post-10Gy resulted in 7% of tumor cells in the corpus callosum, 4% in the striatum, and 60% in the olfactory bulb being CldU positive. Finally, when CldU delivery was begun 20 days post-10Gy approximately 17% of tumor cells in the corpus callosum, 15% in the striatum, and 85% in the olfactory bulb were CldU positive. These data suggest that after irradiation, GBM tumor cells located in the olfactory bulb recover and begin to proliferate sooner than those in the striatum or corpus callosum. As a measure of radiation-induced DNA double strand breaks, γH2AX foci were quantified in the tumor cells located in the corpus callosum, striatum, and olfactory bulb on day 35 post-implantation of NSC11 cells. At 0.5h after irradiation, no difference was detected in the mean number of γH2AX foci per tumor cell in the corpus callosum, striatum, or olfactory bulb; no consistent differences were detected out to 6h post-irradiation. While the mechanism remains to be defined, analysis of tumor cell proliferation indicates a preferential radioresistance of GBM cells located in the olfactory bulb. Citation Format: Cindy R. Timme, Barbara H. Rath, Kevin Camphausen, Philip J. Tofilon. Preferential radioresistance of glioblastoma stem-like tumor cells that migrate to the olfactory bulb [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4171.