Sublethal irradiation promotes migration and invasiveness of glioma cells:Implications for radiotherapy of human glioblastoma

Human malignant gliomas are highly lethal neoplasms. Involved-field radioth erapy is the most important therapeutic measure, Most relapses originate fr om the close vicinity of the irradiated target field. Here, we report that sublethal doses of irradiation enhance the migration and invasiveness of hu man malignant glioma cells, This hitherto unknown biological effect of irra diation is p53 independent, involves enhanced alpha (v)beta (3) integrin ex pression, an altered profile of matrix metalloproteinase-2 and matrix metal loproteinase-9 (MMP-2 and MMP-9) expression and activity, altered membrane type 1 MMP and tissue inhibitor of metalloproteinases-2 expression, and an altered BCL-2/BAX rheostat favoring resistance to apoptosis, BCL-2 gene tra nsfer and irradiation cooperate to enhance migration and invasiveness in a synergistic manner. Sublethal irradiation of rat 9L glioma cells results in the formation of a greater number of tumor satellites in the rat brain in vivo concomitant with enhanced MMP-2 and reduced tissue inhibitor of metall oproteinases-2 expression. Collectively, these data suggest that the curren t concepts of involved-field radiotherapy for malignant glioma need to be r econsidered and that the pharmacological inhibition of migration and invasi on during radiotherapy may represent a new therapeutic approach to improve the therapeutic efficacy of radiotherapy for malignant glioma.