Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma

  • Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.

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Author:Alexander Scholz, Patrick Nikolaus HarterORCiDGND, Sebastian CremerGND, Burak H. Yalcin, Stefanie Gurnik, Maiko Yamaji, Mariangela Di Tacchio, Kathleen Sommer, Peter BaumgartenORCiDGND, Oliver Bähr, Joachim Peter SteinbachORCiDGND, Jörg TrojanORCiDGND, Martin Glas, Ulrich HerrlingerORCiDGND, Dietmar KrexGND, Matthias Meinhardt, Astrid Weyerbrock, Marco Timmer, Roland GoldbrunnerORCiDGND, Martina Deckert, Christian Braun, Jens Schittenhelm, Jochen Früh, Evelyn UllrichORCiDGND, Michel Guy André MittelbronnORCiDGND, Karl PlateGND, Yvonne Reiss
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/26666269
Parent Title (English):EMBO molecular medicine
Place of publication:Weinheim
Document Type:Article
Date of Publication (online):2016/12/21
Date of first Publication:2015/12/14
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/12/21
Tag:anti-angiogenic therapy; glioblastoma; macrophage polarization; therapy resistance; tumor angiogenesis
Page Number:19
First Page:39
Last Page:57
License: This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0