||Effects of Fractionated Radiation on Murine Glioma Stem Cell Metabolism
Satoshi, Fujita ,
Satoru, Osuka ,
Shunsuke, Shibao ,
Kaori, Igarashi ,
Tomoyoshi, SogaOltea, Sampetrean
52 , 2016-6 , The Medical Society of Toho University
Background: Glioma stem cells (GSCs) have an important role in tumor recurrence after treatment. We recently showed that, in a mouse model of glioma, GSCs adapt to repeated radiation exposures by changing their secretory profile and modulating survival signaling. Irradiated GSCs also reduce their rate of proliferation. In the present study we examined whether these changes require a specific adaptation of GSC energy metabolism. Methods: Initial tumors were established in mice by orthotopic implantation of Ink4a/Arf-null neural stem cells transduced with human HRASV12. GSCs isolated from the tumors were exposed (or not) to fractionated radiation (12 fractions of 5 Gy), and five clones in each group of cells were assessed for glucose consumption, lactate production, and content of intracellular metabolites. Results: Rates of glucose consumption and lactate production were lower in clones exposed to radiation than in nonirradiated clones, which suggests a reduction in glycolysis. Among intracellular metabolites, the high concentrations of intermediates of glycolysis and nucleoside metabolism were reduced in irradiated clones, whereas levels of essential amino acids were largely unchanged. Conclusions: Repeated radiation changes the metabolic preferences of GSCs, in conjunction with their slowed proliferation. Future studies should thus investigate intra- and extracellular metabolites, to identify potential diagnostic and therapeutic targets for glioma recurrence.