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Pharmacological targeting of apelin impairs glioblastoma growth

Published version
Peer-reviewed

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Authors

Harford-Wright, E 
Andre-Gregoire, G 
Jacobs, KA 
Treps, L 
Le Gonidec, S 

Abstract

Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours, a subpopulation of highly plastic self-renewing cancer cells exist that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio- and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such angiocrine signals remains unknown. Here, we deployed a mass spectrometry proteomic approach to characterise the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties (GSCs). Genetic and pharmacological targeting of apelin cognate receptor APLNR abrogates apelin- and endothelial-mediated expansion of GSCs and suppresses tumour initiation and growth. Functionally, selective competitive antagonists of APLNR were shown to be safe and effective in lengthening the survival of intracranially xenografted mice. Therefore, the APLN/APLNR signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.

Description

Keywords

APJ, antagonist, apelin, glioblastoma initiating cells, vascular niche, Animals, Apelin, Apelin Receptors, Brain Neoplasms, Cell Proliferation, Cell Survival, Endothelial Cells, Glioblastoma, HEK293 Cells, Humans, In Vitro Techniques, Intercellular Signaling Peptides and Proteins, Mass Spectrometry, Mice, Molecular Targeted Therapy, Proteomics, RNA, Small Interfering, Receptors, G-Protein-Coupled, Xenograft Model Antitumor Assays

Journal Title

Brain

Conference Name

Journal ISSN

0006-8950
1460-2156

Volume Title

Publisher

OUP
Sponsorship
Medical Research Council (MC_PC_13059)
WT107715/Z/15/Z