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 identifi
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 Harter, Sebastian Cremer, Burak H. Yalcin, Stefanie Gurnik, Maiko Yamaji, Mariangela Di Tacchio, Kathleen Sommer, Peter Baumgarten, Oliver Bähr, Joachim Peter Steinbach, Jörg Trojan, Martin Glas, Ulrich Herrlinger, Dietmar Krex, Matthias Meinhardt, Astrid Weyerbrock, Marco Timmer, Roland Goldbrunner, Martina Deckert, Christian Braun, Jens Schittenhelm, Jochen Früh, Evelyn Ullrich, Michel Guy André Mittelbronn, Karl H. Plate, Yvonne Reiss
URN:urn:nbn:de:hebis:30:3-424283
DOI:http://dx.doi.org/10.15252/emmm.201505505
ISSN:1715-4684
ISSN:1757-4676
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=26666269
Parent Title (English):EMBO molecular medicine
Publisher:Wiley-VCH
Place of publication:Weinheim
Document Type:Article
Language:English
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
Volume:8.2016
Issue:1
Pagenumber:19
First Page:39
Last Page:57
Note:
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
HeBIS PPN:425293041
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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