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 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.

• Authors: 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, Zhengping Zhuang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 14 Pg. 11882-93 (May 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25957416 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Basic Helix-Loop-Helix Transcription Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Small Interfering
• endothelial PAS domain-containing protein 1
• Bevacizumab

Topics

• Angiogenesis Inhibitors (pharmacology)
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Bevacizumab (pharmacology)
• Brain Neoplasms (pathology)
• Cell Hypoxia (drug effects, physiology)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (metabolism)
• Epithelial-Mesenchymal Transition (drug effects)
• Gene Knockdown Techniques
• Glioma (pathology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Microfluidic Analytical Techniques
• Neovascularization, Pathologic (metabolism)
• Phenotype
• RNA, Small Interfering
• Signal Transduction (drug effects, physiology)