Selective coexpression of VEGF receptor 2 in EGFRvIII-positive glioblastoma cells prevents cellular senescence and contributes to their aggressive nature
| Autor: | Steven L. Gonias, Karra A. Jones, Andrew S. Gilder, Na Du, Michael A. Banki, Scott R. VandenBerg, Donald P. Pizzo, Michael S. Lam, Aran B. Merati |
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| Rok vydání: | 2015 |
| Předmět: |
EGFRvIII
0301 basic medicine Cancer Research Cell signaling medicine.drug_class Oncology and Carcinogenesis Immunoblotting VEGF receptor-2 Real-Time Polymerase Chain Reaction Tyrosine-kinase inhibitor Mice 03 medical and health sciences EGF receptor medicine cellular senescence Animals Humans Oncology & Carcinogenesis Epidermal growth factor receptor Receptor Cellular Senescence Cell Proliferation Oligonucleotide Array Sequence Analysis Epidermal Growth Factor biology Brain Neoplasms Cell growth glioblastoma Neurosciences Kinase insert domain receptor Immunohistochemistry Vascular Endothelial Growth Factor Receptor-2 ErbB Receptors 030104 developmental biology Oncology Gene Knockdown Techniques Basic and Translational Investigations Cancer research biology.protein Heterografts Neurology (clinical) Signal transduction Glioblastoma Cell aging Signal Transduction |
| Zdroj: | Neuro-oncology, vol 18, iss 5 |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/nov243 |
| Popis: | Author(s): Jones, Karra A; Gilder, Andrew S; Lam, Michael S; Du, Na; Banki, Michael A; Merati, Aran; Pizzo, Donald P; VandenBerg, Scott R; Gonias, Steven L | Abstract: BackgroundIn glioblastoma (GBM), the gene for epidermal growth factor receptor (EGFR) is frequently amplified. EGFR mutations also are common, including a truncation mutation that yields a constitutively active variant called EGFR variant (v)III. EGFRvIII-positive GBM progresses rapidly; however, the reason for this is not clear because the activity of EGFRvIII is attenuated compared with EGF-ligated wild-type EGFR. We hypothesized that EGFRvIII-expressing GBM cells selectively express other oncogenic receptors that support tumor progression.MethodsMining of The Cancer Genome Atlas prompted us to test whether GBM cells in culture, which express EGFRvIII, selectively express vascular endothelial growth factor receptor (VEGFR)2. We also studied human GBM propagated as xenografts. We then applied multiple approaches to test the effects of VEGFR2 on GBM cell growth, apoptosis, and cellular senescence.ResultsIn human GBM, EGFR overexpression and EGFRvIII positivity were associated with increased VEGFR2 expression. In GBM cells in culture, EGFRvIII-initiated cell signaling increased expression of VEGFR2, which prevented cellular senescence and promoted cell cycle progression. The VEGFR-selective tyrosine kinase inhibitor cediranib decreased tumor DNA synthesis, increased staining for senescence-associated β-galactosidase, reduced retinoblastoma phosphorylation, and increased p27(Kip1), all markers of cellular senescence. Similar results were obtained when VEGFR2 was silenced.ConclusionsVEGFR2 expression by GBM cells supports cell cycle progression and prevents cellular senescence. Coexpression of VEGFR2 by GBM cells in which EGFR signaling is activated may contribute to the aggressive nature of these cells. |
| Databáze: | OpenAIRE |
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