2. Academic Validation
  3. Pharmacological targeting of apelin impairs glioblastoma growth

Pharmacological targeting of apelin impairs glioblastoma growth

  • Brain. 2017 Nov 1;140(11):2939-2954. doi: 10.1093/brain/awx253.
Elizabeth Harford-Wright 1 2,  Gwennan Andre-Gregoire 1,  Kathryn A Jacobs 1,  Lucas Treps 2,  Sophie Le Gonidec 3,  Heloise M Leclair 1 2,  Sara Gonzalez-Diest 1 2,  Quentin Roux 1,  François Guillonneau 4,  Delphine Loussouarn 5 6,  Lisa Oliver 5 6,  François M Vallette 6 7,  Fabienne Foufelle 8,  Philippe Valet 3,  Anthony P Davenport 9,  Robert C Glen 10 11,  Nicolas Bidere 1 2,  Julie Gavard 1 2
Affiliations

Affiliations

  • 1 CRCINA, Inserm, Team SOAP, CNRS, Universite de Nantes, Nantes, France.
  • 2 Institut Cochin, Team SOAP, Inserm, CNRS, Universite Paris Descartes, Paris, France.
  • 3 I2MC, Inserm, Universite Paul Sabatier, Toulouse, France.
  • 4 3P5 Proteomics Facility of the Universite Paris Descartes, Paris, France.
  • 5 Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France.
  • 6 CRCINA, Inserm, Universite de Nantes, Nantes, France.
  • 7 Institut de Cancérologie de l'Ouest, René Gauducheau, St Herblain, France.
  • 8 Centre de Recherches des Cordeliers, Inserm, Universite Paris Descartes, Paris, France.
  • 9 Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK.
  • 10 The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK.
  • 11 Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, UK.
PMID: 29053791 DOI: 10.1093/brain/awx253
Abstract

Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours exists a subpopulation of highly plastic self-renewing Cancer cells 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 signals remains unknown. Here, we used a mass spectrometry proteomic approach to characterize 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. Genetic and pharmacological targeting of apelin cognate receptor abrogates apelin- and endothelial-mediated expansion of glioblastoma patient-derived cells with stem-like properties in vitro and suppresses tumour growth in vivo. Functionally, selective competitive antagonists of apelin receptor were shown to be safe and effective in reducing tumour expansion and lengthening the survival of intracranially xenografted mice. Therefore, the apelin/apelin receptor signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.

Keywords

APJ; antagonist; apelin; glioblastoma initiating cells; vascular niche.

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