Oncotarget

Research Papers:

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

Tobias Kessler _, Felix Sahm, Jonas Blaes, Matthias Osswald, Petra Rübmann, David Milford, Severino Urban, Leonie Jestaedt, Sabine Heiland, Martin Bendszus, Anne Hertenstein, Philipp-Niclas Pfenning, Carmen Ruiz de Almodóvar, Antje Wick, Frank Winkler, Andreas von Deimling, Michael Platten, Wolfgang Wick and Markus Weiler

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Oncotarget. 2015; 6:31050-31068. https://doi.org/10.18632/oncotarget.2910

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Abstract

Tobias Kessler1,*, Felix Sahm3,6,*, Jonas Blaes1, Matthias Osswald1,4, Petra Rübmann1, David Milford7, Severino Urban8, Leonie Jestaedt7, Sabine Heiland7, Martin Bendszus7, Anne Hertenstein2,4, Philipp-Niclas Pfenning1, Carmen Ruiz de Almodóvar8, Antje Wick4, Frank Winkler1,4, Andreas von Deimling3,6, Michael Platten2,4, Wolfgang Wick1,4, Markus Weiler1,4,5

1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

2Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

3Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany

5Department of General Neurology, Heidelberg University Hospital, Heidelberg, Germany

6Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany

7Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany

8Biochemistry 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.


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