Scholz, Alexander, Harter, Patrick N. ORCID: 0000-0001-5530-6910, Cremer, Sebastian, Yalcin, Burak H., Gurnik, Stefanie, Yamaji, Maiko, Di Tacchio, Mariangela, Sommer, Kathleen, Baumgarten, Peter, Baehr, Oliver, Steinbach, Joachim P., Trojan, Joerg, Glas, Martin, Herrlinger, Ulrich, Krex, Dietmar, Meinhardt, Matthias, Weyerbrock, Astrid ORCID: 0000-0001-9060-4462, Timmer, Marco, Goldbrunner, Roland, Deckert, Martina, Braun, Christian, Schittenhelm, Jens, Frueh, Jochen T., Ullrich, Evelyn ORCID: 0000-0001-8530-1192, Mittelbronn, Michel, Plate, Karl H. and Reiss, Yvonne (2016). Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol. Med., 8 (1). S. 39 - 58. HOBOKEN: WILEY-BLACKWELL. ISSN 1757-4684

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Abstract

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 bevacizumabtreated 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Scholz, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harter, Patrick N.UNSPECIFIEDorcid.org/0000-0001-5530-6910UNSPECIFIED
Cremer, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yalcin, Burak H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gurnik, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yamaji, MaikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di Tacchio, MariangelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sommer, KathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumgarten, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baehr, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinbach, Joachim P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trojan, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glas, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrlinger, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krex, DietmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meinhardt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weyerbrock, AstridUNSPECIFIEDorcid.org/0000-0001-9060-4462UNSPECIFIED
Timmer, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldbrunner, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deckert, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schittenhelm, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frueh, Jochen T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, EvelynUNSPECIFIEDorcid.org/0000-0001-8530-1192UNSPECIFIED
Mittelbronn, MichelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plate, Karl H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiss, YvonneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-291730
DOI: 10.15252/emmm.201505505
Journal or Publication Title: EMBO Mol. Med.
Volume: 8
Number: 1
Page Range: S. 39 - 58
Date: 2016
Publisher: WILEY-BLACKWELL
Place of Publication: HOBOKEN
ISSN: 1757-4684
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NEWLY-DIAGNOSED GLIOBLASTOMA; TUMOR-ASSOCIATED MACROPHAGES; ANTI-ANGIOGENIC THERAPY; OVARIAN-CANCER; TIE2-EXPRESSING MONOCYTES; ANTIANGIOGENIC THERAPY; SERUM ANGIOPOIETIN-2; DISEASE PROGRESSION; COLORECTAL-CANCER; POTENT ANTITUMORMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/29173

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