title: Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma.
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.
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scholz
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Cremer
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Burak H
authors.initials: BH
authors.lastname: Yalcin
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gurnik
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Maiko
authors.initials: M
authors.lastname: Yamaji
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Di Tacchio
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sommer
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany Department of Neurosurgery, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Baumgarten
authors.affiliation: Senckenberg Institute of Neurooncology, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bähr
authors.affiliation: German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany Senckenberg Institute of Neurooncology, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Medical Clinic I, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Trojan
authors.affiliation: Klinische Kooperationseinheit Neuroonkologie, Robert Janker Klinik, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Glas
authors.affiliation: Neurologische Universitätsklinik Bonn, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Herrlinger
authors.affiliation: Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Krex
authors.affiliation: Institut für Pathologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Meinhardt
authors.affiliation: Klinik für Neurochirurgie, Universitätsklinikum Freiburg, Freiburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Weyerbrock
authors.affiliation: Zentrum für Neurochirurgie, Uniklinik Köln, Köln, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Timmer
authors.affiliation: Zentrum für Neurochirurgie, Uniklinik Köln, Köln, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Goldbrunner
authors.affiliation: Institut für Neuropathologie, Uniklinik Köln, Köln, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Deckert
authors.affiliation: Zentrum für Neuroonkologie, Universitätsklinik Tübingen, Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Braun
authors.affiliation: Abteilung Neuropathologie, Universitätsklinik Tübingen, Tübingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Schittenhelm
authors.affiliation: 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.
authors.forename: Jochen T
authors.initials: JT
authors.lastname: Frueh
authors.affiliation: 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.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ullrich
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.affiliation: 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.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Reiss
mesh_terms: D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D000818:Animals; D000068258:Bevacizumab / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D011956:Receptors, Cell Surface / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000494:pharmacology / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; C551398:trebananib
keywords: anti‐angiogenic therapy; glioblastoma; macrophage polarization; therapy resistance; tumor angiogenesis