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Extracellular vesicle-transported Semaphorin3A promotes vascular permeability in glioblastoma

Oncogene volume 35, pages 2615–2623 (2016)Cite this article

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Abstract

Glioblastoma are malignant highly vascularized brain tumours, which feature large oedema resulting from tumour-promoted vascular leakage. The pro-permeability factor Semaphorin3A (Sema3A) produced within glioblastoma has been linked to the loss of endothelial barrier integrity. Here, we report that extracellular vesicles (EVs) released by patient-derived glioblastoma cells disrupt the endothelial barrier. EVs expressed Sema3A at their surface, which accounted for in vitro elevation of brain endothelial permeability and in vivo vascular permeability, in both skin and brain vasculature. Blocking Sema3A or its receptor Neuropilin1 (NRP1) hampered EV-mediated permeability. In vivo models using ectopically and orthotopically xenografted mice revealed that Sema3A-containing EVs were efficiently detected in the blood stream. In keeping with this idea, sera from glioblastoma multiforme (GBM) patients also contain high levels of Sema3A carried in the EV fraction that enhanced vascular permeability, in a Sema3A/NRP1-dependent manner. Our results suggest that EV-delivered Sema3A orchestrates loss of barrier integrity in glioblastoma and may be of interest for prognostic purposes.

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Acknowledgements

We are thankful to present and past members of the team, especially to Héloise Leclair and Armelle Le Guelte. We are grateful to Robin Lombard (Myltenyi Biotech, Paris, France) for technical assistance with the MacsQuant cytometer. We are also grateful to PO Couraud and F Niedergang’s team (Institut Cochin, Paris, France) for helpful discussion and reagents. This research was funded by: Fondation pour la Recherche Médicale, Institut National du Cancer INCA_6508, Ligue nationale contre le cancer comité de Paris, Region Pays-de-la-Loire, Nantes Metropole. LT is supported by doctoral fellowship from Universite Paris Descartes. EMGM, EHW and SA are supported by post-doctoral fellowships from Ligue nationale contre le cancer, Canceropole Ile-de-France and Fondation ARC Association pour la Recherche sur le Cancer, respectively.

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Authors and Affiliations

  1. CNRS, UMR8104, Paris, France

    L Treps, E Harford-Wright, E M Galan-Moya, A Schmitt, S Azzi, A Citerne, N Bidère & J Gavard

  2. Inserm, U1016, Paris, France

    L Treps, E Harford-Wright, E M Galan-Moya, A Schmitt, S Azzi, A Citerne, N Bidère & J Gavard

  3. Universite Paris Descartes, Sorbonne Paris Cite, Paris, France

    L Treps, E Harford-Wright, E M Galan-Moya, A Schmitt, S Azzi, A Citerne, N Bidère & J Gavard

  4. Hopital d'Instruction des Armees du Val-de-Grace, Service de Neurologie, Paris Cedex, France

    S Edmond & D Ricard

  5. INSERM, U892, Nantes, France

    E Harford-Wright, N Bidère & J Gavard

  6. CNRS, UMR6299, Nantes, France

    E Harford-Wright, N Bidère & J Gavard

  7. University of Nantes, Nantes, France

    E Harford-Wright, N Bidère & J Gavard

  8. CNRS, UMR8257, COGNAC G, Paris, France

    D Ricard

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  1. L Treps
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Correspondence to J Gavard.

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Treps, L., Edmond, S., Harford-Wright, E. et al. Extracellular vesicle-transported Semaphorin3A promotes vascular permeability in glioblastoma. Oncogene 35, 2615–2623 (2016). https://doi.org/10.1038/onc.2015.317

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