Abstract
Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), can attenuate tumor-associated edema and improve patient symptoms but based on magnetic resonance imaging, is associated with non-enhancing tumor progression and possibly gliosarcoma differentiation. To gain insight into these findings, we investigated the role of hypoxia and epithelial-mesenchymal transition (EMT)-associated proteins in GBM. Tumor markers of hypoxia and EMT were upregulated in bevacizumab-treated tumors from GBM patients compared to untreated counterparts. Exposure of glioma cells to 1% oxygen tension increased cell proliferation, expression of EMT-associated proteins and enhanced cell migration in vitro. These phenotypic changes were significantly attenuated by pharmacologic knockdown of hypoxia-inducible Factor 1α (HIF1α) or HIF2α, indicating that HIFs represent a therapeutic target for mesenchymal GBM cells. These findings provide insights into potential development of novel therapeutic targeting of angiogenesis-specific pathways in GBM.
Highlights
Glioblastoma (GBM) is the most common adult primary nervous system tumor
To test the hypothesis that anti-angiogenic therapy can induce an epithelial-mesenchymal transition (EMT)-like process through hypoxia in GBM, we analyzed tumor tissues from three recurrent GBM patients for markers of hypoxia and EMT before and after bevacizumab treatment
At 48 hours under hypoxia, each EMT-associated protein was upregulated, and expression was blocked by treatment with a hypoxia-inducible factors (HIFs) inhibitor. These findings indicate that hypoxia enhances the expression of proteins that induce EMT and expression of these proteins is subject to inhibition by pharmacologic blockade of HIFs
Summary
Despite advances in surgical resection, radiation and chemotherapy, GBM remains one of the most deadly human neoplasms. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), has been shown to improve progression-free survival in patients with recurrent glioblastoma [2,3,4]. As one of the most highly www.impactjournals.com/oncotarget vascular cancers, GBMs express high levels of VEGF, in areas of necrosis and hypoxia [5, 6]. The increased levels of VEGF expression and vascular density in GBM make angiogenesis an attractive therapeutic target. Clinical trials have demonstrated that bevacizumab is a therapeutic option for recurrent GBM patients who have failed previous radiation and chemotherapy [3, 7]
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