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[Cancer Research 61, 2744-2750, March 15, 2001]
© 2001 American Association for Cancer Research

Tumor Biology

Sublethal Irradiation Promotes Migration and Invasiveness of Glioma Cells

Implications for Radiotherapy of Human Glioblastoma1

Christine Wild-Bode, Michael Weller, Andreas Rimner, Johannes Dichgans and Wolfgang Wick2

Department of Neurology, Laboratory of Molecular Neuro-Oncology, University of Tübingen, Medical School, D-72076 Tübingen, Germany

Human malignant gliomas are highly lethal neoplasms. Involved-field radiotherapy is the most important therapeutic measure. Most relapses originate from the close vicinity of the irradiated target field. Here, we report that sublethal doses of irradiation enhance the migration and invasiveness of human malignant glioma cells. This hitherto unknown biological effect of irradiation is p53 independent, involves enhanced {alpha}vß3 integrin expression, an altered profile of matrix metalloproteinase-2 and matrix metalloproteinase-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 transfer 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 metalloproteinases-2 expression. Collectively, these data suggest that the current concepts of involved-field radiotherapy for malignant glioma need to be reconsidered and that the pharmacological inhibition of migration and invasion during radiotherapy may represent a new therapeutic approach to improve the therapeutic efficacy of radiotherapy for malignant glioma.




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