Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma

• Published in: Oncotarget Vol. 6; no. 31; pp. 31050 - 31068
• Main Authors: Kessler, Tobias, Sahm, Felix, Blaes, Jonas, Osswald, Matthias, Rübmann, Petra, Milford, David, Urban, Severino, Jestaedt, Leonie, Heiland, Sabine, Bendszus, Martin, Hertenstein, Anne, Pfenning, Philipp-Niclas, de Almodóvar, Carmen Ruiz, Wick, Antje, Winkler, Frank, von Deimling, Andreas, Platten, Michael, Wick, Wolfgang, Weiler, Markus
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 13.10.2015
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Bevacizumab - pharmacology; Brain Neoplasms - drug therapy; Brain Neoplasms - enzymology; Brain Neoplasms - genetics; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glioma - drug therapy; Glioma - enzymology; Glioma - genetics; Glioma - mortality; Glioma - pathology; Humans; Kaplan-Meier Estimate; Mice, Nude; Neoplasm Invasiveness; Neovascularization, Pathologic; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - genetics; Research Paper; Signal Transduction - drug effects; Time Factors; Transfection; Tumor Burden - drug effects; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Xenograft Model Antitumor Assays; phosphatase and tensin homolog deleted on chromosome 10 (PTEN); vascular endothelial growth factor receptor (VEGFR)-2; glioblastoma; invasion; angiogenesis
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2910

Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.