Article
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
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Published: | May 8, 2019 |
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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.