Abstract
INTRODUCTION: Normal brain tissue is exposed to 5-8% oxygen whilst the average oxygen level within brain tumours is just 1% (hypoxia). Hypoxia is associated with the increased malignancy, invasiveness, and treatment resistance of brain tumours. Paradoxically, hypoxia has also been shown to induce cell cycle arrest in certain cells; however the impact of pathophysiological hypoxia on tumour cell proliferation is poorly understood. The aim of this project was to investigate the consequences of different oxygen levels on glioblastoma (GBM) cell proliferation and survival. GBM is an aggressive brain tumour with an extremely poor prognosis. METHOD: GBM cell lines were exposed to a range of oxygen tensions and their cell cycle distribution and survival was assessed using flow cytometry. Changes in the expression level of genes involved in regulation of the cell cycle were quantified by qRT-PCR. RESULTS: Results indicate that GBM proliferation and survival is unaffected by long-term exposure to pathophysiological levels of oxygen (1% O2). Cell cycle arrest and/or cell death could only be detected when cells were exposed to severe hypoxia (0.1% O2). Sensitivity to severe hypoxia was associated with increased expression of the cyclin-dependent kinase inhibitor protein p21. CONCLUSION: These findings demonstrate that the pro-tumorigenic effects of pathophysiological hypoxia are not balanced out by reduced cellular proliferation, strengthening the association between hypoxia and tumour malignancy. This helps to explain how a hypoxic tumour such as GBM can be incredibly fast growing and aggressive.