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EMBO Mol Med. 2016 Jan 1;8(1):39-57. doi: 10.15252/emmm.201505505.

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

Author information

1
Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
2
Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany.
3
Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany Department of Neurosurgery, Goethe University Medical School, Frankfurt, Germany.
4
Senckenberg Institute of Neurooncology, Goethe University Medical School, Frankfurt, Germany.
5
German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany Senckenberg Institute of Neurooncology, Goethe University Medical School, Frankfurt, Germany.
6
Medical Clinic I, Goethe University Medical School, Frankfurt, Germany.
7
Klinische Kooperationseinheit Neuroonkologie, Robert Janker Klinik, Bonn, Germany.
8
Neurologische Universitätsklinik Bonn, Bonn, Germany.
9
Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
10
Institut für Pathologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
11
Klinik für Neurochirurgie, Universitätsklinikum Freiburg, Freiburg, Germany.
12
Zentrum für Neurochirurgie, Uniklinik Köln, Köln, Germany.
13
Institut für Neuropathologie, Uniklinik Köln, Köln, Germany.
14
Zentrum für Neuroonkologie, Universitätsklinik Tübingen, Tübingen, Germany.
15
Abteilung Neuropathologie, Universitätsklinik Tübingen, Tübingen, Germany.
16
LOEWE Center for Cell and Gene Therapy, Goethe University Medical School, Frankfurt, Germany Pediatric Hematology & Oncology, Children's Hospital, Goethe University Medical School, Frankfurt, Germany.
17
Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany yvonne.reiss@kgu.de.

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 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.

KEYWORDS:

anti‐angiogenic therapy; glioblastoma; macrophage polarization; therapy resistance; tumor angiogenesis

PMID:
26666269
PMCID:
PMC4718155
DOI:
10.15252/emmm.201505505
[Indexed for MEDLINE]
Free PMC Article

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