gms | German Medical Science

70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

12.05. - 15.05.2019, Würzburg

Pro-invasive side effects of bevacizumab and ramucirumab therapy in proneural and classical GBM is mediated by apelin signalling and reducible by apelin receptor blockade

Proinvasive Nebenwirkungen von Bevacizumab- und Ramucirumabtherapie beim proneuralen und klassischen Subtyp des Glioblastoms werden durch den Apelinsignalweg vermittelt und können durch Apelinrezeptorblockade reduziert werden

Meeting Abstract

  • presenting/speaker Veit Stöcklein - Klinikum der Universität München, Neurochirurgische Klinik und Poliklinik, München, Deutschland; Deutsches Krebsforschungszentrum (DKFZ), Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partnerstandort München, München, Deutschland
  • Min Li - Klinikum der Universität München, Neurochirurgische Klinik und Poliklinik, München, Deutschland
  • Patrick N. Harter - Universitätsklinikum Frankfurt, Edinger-Institut, Frankfurt, Deutschland; Deutsches Krebsforschungszentrum (DKFZ), Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partnerstandort Frankfurt, Frankfurt, Deutschland
  • Nina Zdouc - Klinikum der Universität München, Neurochirurgische Klinik und Poliklinik, München, Deutschland
  • Michel Mittelbronn - Laboratoire national de santé (LNS), Department of Anatomic and Molecular Pathology, Luxembourg Centre of Neuropathology, Dudelange, Luxembourg
  • Jörg-Christian Tonn - Klinikum der Universität München, Neurochirurgische Klinik und Poliklinik, München, Deutschland; Deutsches Krebsforschungszentrum (DKFZ), Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partnerstandort München, München, Deutschland
  • Rainer Glass - Klinikum der Universität München, Neurochirurgische Klinik und Poliklinik, München, Deutschland
  • Roland Kälin - Klinikum der Universität München, Neurochirurgische Klinik und Poliklinik, München, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie. Würzburg, 12.-15.05.2019. Düsseldorf: German Medical Science GMS Publishing House; 2019. DocP080

doi: 10.3205/19dgnc418, urn:nbn:de:0183-19dgnc4183

Published: May 8, 2019

© 2019 Stöcklein et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Objective: Anti-angiogenic therapy of glioblastoma (GBM) blocking Vascular endothelial growth factor-A (VEGFA) often resulted in accelerated tumor-cell invasion and upregulation of alternative angiogenic pathways. Here, we studied the role of the proangiogenic apelin receptor (APLNR) and its cognate ligand apelin on VEGF-A / VEGFR2-centered GBM therapy.

Methods: We investigated expression-levels and localization of apelin/ APLNR in anti-VEGFA/anti-VEGFR2 treated mouse and human GBM samples using in situ hybridization and qPCR. For functional studies of apelin-signaling we performed orthotopic implantation of patient-derived and mouse subtype-specific GBM stem cell cultures and employed genetic and pharmacological blockade for apelin/APLNR and VEGFA/VEGFR2-signaling in our in vivo and in vitro experiments.

Results: A direct relation of apelin and VEGF-A levels was observed in a clinical and preclinical analysis. We found that apelin was downregulated in samples post-bevacizumab therapy as compared to samples of the same patient pre-treatment. In mouse models, treatment with anti-VEGFA or anti-VEGFR2 antibodies led to downregulation of apelin. In orthotopic implantation models, a decrease in apelin-levels by knockdown or knockout massively reduced GBM vascularization of the proneural or classical type, while controls maintained apelin-dependent angiogenesis. However, reducing apelin expression levels resulted in strongly accelerated GBM cell invasion. Importantly, co-targeting of VEGFR2 and APLNR synergistically improved survival of murine models of glioblastoma by 65% compared to controls. Immunohistological analysis of tumors with comparable overall tumor volume showed that administration of anti-VEGFR2 alone had a pro-invasive effect (by 77%) while the APLNR blockade reduced the invasive volume (by 74%) significantly compared with control mice and combined treatment (by 66%) compared with anti-VEGFR2 treatment alone.

Conclusion: We revealed a central role of the apelin/APLNR signaling pathway in anti-angiogenic treatment of glioblastoma and in countering resistance to bevacizumab (anti-VEGF-A antibody) and ramucirumab (anti-VEGFR2 antibody). We show that apelin/APLNR signaling controls glioblastoma angiogenesis and invasion, and that both pathological features are blunted by APLNR blockade. We therefore suggest that APLNR blockade can improve the efficiency of established anti-angiogenic treatments.