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

EMBO Molecular Medicine

Alexander Scholz¹¹  Patrick N Harter¹¹  Sebastian Cremer¹¹  Burak H Yalcin¹¹  Stefanie Gurnik¹¹  Maiko Yamaji¹¹  Mariangela Di Tacchio¹¹  Kathleen Sommer¹¹  Peter Baumgarten¹¹  Oliver Bähr⁶  Joachim P Steinbach⁸  Jörg Trojan²  Martin Glas¹³  Ulrich Herrlinger¹  Dietmar Krex⁵  Matthias Meinhardt¹²  Astrid Weyerbrock⁴  Marco Timmer^7,11  Roland Goldbrunner^7,11  Martina Deckert^3,11  Christian Braun^9,11  Jens Schittenhelm^11,14  Jochen T Frueh^10,11  Evelyn Ullrich^10,11  Michel Mittelbronn¹¹  Karl H Plate¹¹ 

[1] Neurologische Universitätsklinik Bonn, Bonn, Germany;Medical Clinic I, Goethe University Medical School, Frankfurt, Germany;Institut für Neuropathologie, Uniklinik Köln, Köln, Germany;Klinik für Neurochirurgie, Universitätsklinikum Freiburg, Freiburg, Germany;Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany;Senckenberg Institute of Neurooncology, Goethe University Medical School, Frankfurt, Germany;Zentrum für Neurochirurgie, Uniklinik Köln, Köln, Germany;German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany;Zentrum für Neuroonkologie, Universitätsklinik Tübingen, Tübingen, Germany;LOEWE Center for Cell and Gene Therapy, Goethe University Medical School, Frankfurt, Germany;Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany;Institut für Pathologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany;Klinische Kooperationseinheit Neuroonkologie, Robert Janker Klinik, Bonn, Germany;Abteilung Neuropathologie, Universitätsklinik Tübingen, Tübingen, Germany

关键词: anti‐angiogenic therapy;    glioblastoma;    macrophage polarization;    therapy resistance;    tumor angiogenesis;   

DOI  :  10.15252/emmm.201505505

来源: Wiley

【 摘 要 】

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.

Synopsis

While recurrent glioblastoma is treated by inhibiting angiogenesis, resistance limits therapeutic efficacy. Angiopoietin-2 (Ang-2), a potent endothelium-derived angiogenesis factor and regulator of myeloid cell infiltration, is a therapeutic target for treating naive and bevacizumab-resistant glioblastoma.

• The therapeutic benefit of co-targeting Ang-2 and VEGF signaling (using AMG386 and aflibercept/VEGF-trap) is shown in mouse models of GBM.
• Ang-2 and VEGF combination therapy decreased GBM angiogenesis and permeability, improved vascular maturation, and limited the number of tumor-associated macrophages.
• Numbers of CD206⁺ (M2-like) macrophages remained high upon therapy, suggestive of subsequent targeting of M2-like macrophages in bevacizumab-resistant GBM.
• Inhibition of Ang-2, either alone or in combination with VEGF inhibition is of potential use to overcome resistance in GBM patients that have failed bevacizumab therapy.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.