Activation of hypoxia signaling induces phenotypic transformation of glioma cells: implications for bevacizumab antiangiogenic therapy Journal Article

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Authors: Xu, H.; Rahimpour, S.; Nesvick, C. L.; Zhang, X; Ma, J.; Zhang, M; Zhang, G.; Wang, L; Yang, C.; Hong, C. S.; Germanwala, A. V.; Elder, J. B.; Ray-Chaudhury, A.; Yao, Y; Gilbert, M. R.; Lonser, R. R.; Heiss, J. D.; Brady, R. O.; Mao, Y.; Qin, J.; Zhuang, Z.
Article Title: Activation of hypoxia signaling induces phenotypic transformation of glioma cells: implications for bevacizumab antiangiogenic therapy
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 1alpha (HIF1alpha) or HIF2alpha, 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.
Journal Title: Oncotarget
Volume: 6
Issue: 14
ISSN: 1949-2553; 1949-2553
Publisher: Unknown  
Date Published: 2015
Start Page: 11882
End Page: 11893
Language: ENG
DOI/URL:

3592
Notes: LR: 20150510; JID: 101532965; OTO: NOTNLM; 2015/02/12 [received]; 2015/02/19 [accepted]; aheadofprint