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 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.affiliation: Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
authors.forename: Shervin
authors.initials: S
authors.lastname: Rahimpour
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
authors.forename: Cody L
authors.initials: CL
authors.lastname: Nesvick
authors.affiliation: Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Dalian Medical University, Dalian, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hong
authors.affiliation: Department of Neurological Surgery, Loyola University Medical Center, Chicago, Illinois, USA.
authors.forename: Anand V
authors.initials: AV
authors.lastname: Germanwala
authors.affiliation: Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: J Bradley
authors.initials: JB
authors.lastname: Elder
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
authors.forename: Abhik
authors.initials: A
authors.lastname: Ray-Chaudhury
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Neuro-Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.affiliation: Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Heiss
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Qin
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D000068258:Bevacizumab / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D046210:Microfluidic Analytical Techniques; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010641:Phenotype; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D000068258:Bevacizumab; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: bevacizumab; epithelial-mesenchymal transition; glioblastoma; hypoxia-inducible factor; pathologic angiogenesis