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

// Tobias Kessler 1, * , Felix Sahm 3, 6, * , Jonas Blaes 1 , Matthias Osswald 1, 4 , Petra Rubmann 1 , David Milford 7 , Severino Urban 8 , Leonie Jestaedt 7 , Sabine Heiland 7 , Martin Bendszus 7 , Anne Hertenstein 2, 4 , Philipp-Niclas Pfenning 1 , Carmen Ruiz de Almodovar 8 , Antje Wick 4 , Frank Winkler 1, 4 , Andreas von Deimling 3, 6 , Michael Platten 2, 4 , Wolfgang Wick 1, 4 , Markus Weiler 1, 4, 5 1 Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 4 Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany 5 Department of General Neurology, Heidelberg University Hospital, Heidelberg, Germany 6 Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany 7 Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany 8 Biochemistry Center Heidelberg University, Heidelberg, Germany * These authors have contributed equally to this work Correspondence to: Markus Weiler, e-mail: m.weiler@dkfz.de Wolfgang Wick, e-mail: wolfgang.wick@med.uni-heidelberg.de Keywords: angiogenesis, glioblastoma, invasion, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), vascular endothelial growth factor receptor (VEGFR)-2 Received: October 26, 2014      Accepted: December 14, 2014      Published: February 19, 2015 ABSTRACT 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.