Priority Research Papers:

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

Hui Xu, Shervin Rahimpour, Cody L. Nesvick, Xu Zhang, Jingyun Ma, Min Zhang, Ge Zhang, Li Wang, Chunzhang Yang, Christopher S. Hong, Anand V. Germanwala, J. Bradley Elder, Abhik Ray-Chaudhury, Yu Yao, Mark R. Gilbert, Russell R. Lonser, John D. Heiss, Roscoe O. Brady, Ying Mao, Jianhua Qin and Zhengping Zhuang _

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Oncotarget. 2015; 6:11882-11893. https://doi.org/10.18632/oncotarget.3592

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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

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


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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