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Activation of hypoxia signaling induces phenotypic transformation of glioma cells: implications for bevacizumab antiangiogenic therapy
- Source :
- Oncotarget
- Publication Year :
- 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.
- Subjects :
- Pathology
medicine.medical_specialty
Gliosarcoma
Epithelial-Mesenchymal Transition
Angiogenesis Inhibitors
Biology
bevacizumab
chemistry.chemical_compound
Glioma
Cell Line, Tumor
medicine
Basic Helix-Loop-Helix Transcription Factors
Humans
Epithelial–mesenchymal transition
RNA, Small Interfering
hypoxia-inducible factor
Neovascularization, Pathologic
pathologic angiogenesis
Brain Neoplasms
glioblastoma
Cell migration
Microfluidic Analytical Techniques
medicine.disease
Hypoxia-Inducible Factor 1, alpha Subunit
Cell Hypoxia
Oxygen tension
Vascular endothelial growth factor
Cell Transformation, Neoplastic
Phenotype
Oncology
Hypoxia-inducible factors
chemistry
Tumor progression
Gene Knockdown Techniques
Cancer research
Signal Transduction
Priority Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 6
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....d1f11ef520fe401d7535a5b76515d76c