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Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma
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 tre...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741588/ https://www.ncbi.nlm.nih.gov/pubmed/25682871 |
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author | 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 |
author_facet | 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 |
author_sort | Kessler, Tobias |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4741588 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-47415882016-03-03 Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma 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 Oncotarget Research Paper 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. Impact Journals LLC 2015-02-19 /pmc/articles/PMC4741588/ /pubmed/25682871 Text en Copyright: © 2015 Kessler et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper 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 Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma |
title | Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma |
title_full | Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma |
title_fullStr | Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma |
title_full_unstemmed | Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma |
title_short | Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma |
title_sort | glioma cell vegfr-2 confers resistance to chemotherapeutic and antiangiogenic treatments in pten-deficient glioblastoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741588/ https://www.ncbi.nlm.nih.gov/pubmed/25682871 |
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