Priority Research Papers:
Activation of hypoxia signaling induces phenotypic transformation of glioma cells: implications for bevacizumab antiangiogenic therapy
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Hui Xu1, Shervin Rahimpour2, Cody L. Nesvick2, Xu Zhang1, Jingyun Ma1, Min Zhang1, Ge Zhang3, Li Wang1, Chunzhang Yang2, Christopher S. Hong2, Anand V. Germanwala4, J. Bradley Elder5, Abhik Ray-Chaudhury2, Yu Yao6, Mark R. Gilbert7, Russell R. Lonser5, John D. Heiss2, Roscoe O. Brady2, Ying Mao6, Jianhua Qin1 and Zhengping Zhuang2
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
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
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.
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