TY  - JOUR
A1  - Scholz, Alexander
A1  - Harter, Patrick Nikolaus
A1  - Cremer, Sebastian
A1  - Yalcin, Burak H.
A1  - Gurnik, Stefanie
A1  - Yamaji, Maiko
A1  - Di Tacchio, Mariangela
A1  - Sommer, Kathleen
A1  - Baumgarten, Peter
A1  - Bähr, Oliver
A1  - Steinbach, Joachim Peter
A1  - Trojan, Jörg
A1  - Glas, Martin
A1  - Herrlinger, Ulrich
A1  - Krex, Dietmar
A1  - Meinhardt, Matthias
A1  - Weyerbrock, Astrid
A1  - Timmer, Marco
A1  - Goldbrunner, Roland
A1  - Deckert, Martina
A1  - Braun, Christian
A1  - Schittenhelm, Jens
A1  - Früh, Jochen
A1  - Ullrich, Evelyn
A1  - Mittelbronn, Michel Guy André
A1  - Plate, Karl
A1  - Reiss, Yvonne
T1  - Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma
T2  - EMBO molecular medicine
N2  - 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.
KW  - anti-angiogenic therapy
KW  - glioblastoma
KW  - macrophage polarization
KW  - therapy resistance
KW  - tumor angiogenesis
Y1  - 2015
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/42428
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-424283
SN  - 1715-4684
SN  - 1757-4676
N1  - 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
VL  - 8.2016
IS  - 1
SP  - 39
EP  - 57
PB  - Wiley-VCH
CY  - Weinheim
ER  -