370 Hypoxic Conditions and Hypoxia-Inducible Factor 1-Alpha are Critical in the Radioresistance of Meningioma

Abstract

Abstract INTRODUCTION Meningiomas are common benign intracranial neoplasms treated with a combination of surgical resection, radiotherapy, and chemotherapy. Hypoxia-inducible factor 1 alpha (HIF1A) can predict disease aggressiveness, response to oxygen tension and regulate meningioma pathogenesis. The role of HIF1A and hypoxia was explored in the radiation resistance of meningioma, hypothesizing that HIF1A confers resistance to radiotherapy in meningiomas and that oxygen tension is key to radiation responsiveness. METHODS Various primary meningioma cell lines were studied (IOMM-LE, JEN, GAR, SAM). GAR primary cell lines were utilized in addition to a shRNA-HIF1A knockdown (GAR1589). Cell proliferation, viability, and apoptosis were evaluated in response to radiation in both normoxia (21% O2) and hypoxia (1% O2). RESULTS >Doubling times of the various meningioma cell lines ranged from 19.5 to 213.2 hours. Cell density impacted responsiveness to radiation, with confluent cells showing greater dose tolerance before reduced proliferation. In normoxic environments, HIF1A knockout resulted in increased susceptibility to single radiation fractions of 2 Gy (P = 0.05) and 10 Gy (P = 0.02); however, both cells had strong susceptibility at 20 Gy. Hypoxic environments reduced the viability differences between GAR and GAR1589 cells and slightly increased GAR cell viability at 2 Gy (P < 0.05). Fractionated radiotherapy (2 Gy) daily showed reduced GAR and GAR1589 cell viability in normoxia and hypoxia. Cell viability for GAR1589 at 3 fractions of 2-Gy radiation was reduced, but this effect was eliminated in hypoxic environments. Apoptosis was increased in GAR1589 cells at baseline and with increased fractions of radiation; however, this effect was reduced in hypoxic conditions. CONCLUSION These results support important findings for meningioma response to radiation, including 1) importance of cell density, 2) dependence on HIF1A mutation, and 3) a critical role for oxygen tension. These results may be helpful in understanding the mechanisms of meningioma resistance to radiation and serve as a model to trial novel adjuvant therapies and treatment types.