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

// Hui Xu 1 , Shervin Rahimpour 2 , Cody L. Nesvick 2 , Xu Zhang 1 , Jingyun Ma 1 , Min Zhang 1 , Ge Zhang 3 , Li Wang 1 , Chunzhang Yang 2 , Christopher S. Hong 2 , Anand V. Germanwala 4 , J. Bradley Elder 5 , Abhik Ray-Chaudhury 2 , Yu Yao 6 , Mark R. Gilbert 7 , Russell R. Lonser 5 , John D. Heiss 2 , Roscoe O. Brady 2 , Ying Mao 6 , Jianhua Qin 1 and Zhengping Zhuang 2 1 Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China 2 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA 3 Department of Immunology, Dalian Medical University, Dalian, China 4 Department of Neurological Surgery, Loyola University Medical Center, Chicago, Illinois, USA 5 Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio, USA 6 Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China 7 Department of Neuro-Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to: Ying Mao, email: // Jianhua Qin, email: // Zhengping Zhuang, email: // Keywords : glioblastoma, bevacizumab, epithelial-mesenchymal transition, pathologic angiogenesis, hypoxia-inducible factor Received : February 12, 2015 Accepted : February 19, 2015 Published : March 14, 2015 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.