title: Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma.
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.
authors: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Tobias
authors: T
authors: Kessler
authors: Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Felix
authors: F
authors: Sahm
authors: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Jonas
authors: J
authors: Blaes
authors: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors: Matthias
authors: M
authors: Osswald
authors: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Petra
authors: P
authors: Rübmann
authors: Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
authors: David
authors: D
authors: Milford
authors: Biochemistry Center Heidelberg University, Heidelberg, Germany.
authors: Severino
authors: S
authors: Urban
authors: Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Leonie
authors: L
authors: Jestaedt
authors: Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Sabine
authors: S
authors: Heiland
authors: Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Martin
authors: M
authors: Bendszus
authors: Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors: Anne
authors: A
authors: Hertenstein
authors: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Philipp-Niclas
authors: PN
authors: Pfenning
authors: Biochemistry Center Heidelberg University, Heidelberg, Germany.
authors: Carmen
authors: C
authors: Ruiz de Almodóvar
authors: Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors: Antje
authors: A
authors: Wick
authors: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors: Frank
authors: F
authors: Winkler
authors: Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Andreas
authors: A
authors: von Deimling
authors: Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors: Michael
authors: M
authors: Platten
authors: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors: Wolfgang
authors: W
authors: Wick
authors: Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology at the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.|Department of General Neurology, Heidelberg University Hospital, Heidelberg, Germany.
authors: Markus
authors: M
authors: Weiler
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D003606:Dacarbazine; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077204:Temozolomide
keywords: angiogenesis; glioblastoma; invasion; phosphatase and tensin homolog deleted on chromosome 10 (PTEN); vascular endothelial growth factor receptor (VEGFR)-2