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BMP9 counteracts the tumorigenic and pro-angiogenic potential of glioblastoma

Cell Death & Differentiationvolume 25pages18081822 (2018) | Download Citation

Abstract

Glioblastoma multiforme (GBM) is a highly vascularized and aggressive brain tumor, with a strong ability to disseminate and invade the surrounding parenchyma. In addition, a subpopulation of GBM stem cells has been reported to possess the ability to transdifferentiate into tumor-derived endothelial cells (TDECs), supporting the resistance to anti-angiogenic treatments of newly formed blood vessels. Bone Morphogenetic Protein 9 (BMP9) is critically involved in the processes of cancer cell differentiation, invasion and metastasis, representing a potential tool in order to impair the intrinsic GBM aggressiveness. Here we demonstrate that BMP9 is able to trigger the activation of SMADs in patient-derived GBM cells, and to strongly inhibit proliferation and invasion by reducing the activation of PI3K/AKT/MAPK and RhoA/Cofilin pathways, respectively. Intriguingly, BMP9 treatment is sufficient to induce a strong differentiation of GBM stem-like cells and to significantly counteract the already reported process of GBM cell transdifferentiation into TDECs not only in in vitro mimicked TDEC models, but also in vivo in orthotopic xenografts in mice. Additionally, we describe a strong BMP9-mediated inhibition of the whole angiogenic process engaged during GBM tumor formation. Based on these results, we believe that BMP9, by acting at multiple levels against GBM cell aggressiveness, can be considered a promising candidate, to be further developed, for the future therapeutic management of GBM.

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Acknowledgements

We are grateful to Dr. Luisa Galla, Dr. Claudia Lodovichi (Venetian Institute of Molecular Medicine—VIMM, Padova, Italy., National Research Council—CNR, Neuroscience Institute, Milan, Italy) and Dr. Ludovico Scenna (designed Veterinarian, University of Padova) for technical help in stereotaxic surgery and mice perfusion techniques. Moreover, we thank the Laboratory of Immunopathology and Molecular Biology of The Kidney, Department of Woman and Children Health, University of Padova, for invaluable assistance in histological procedures. This work was supported by funds from Cassa di Risparmio di Padova e Rovigo (CARIPARO) Foundation (Project no. IRP13/05) (to GB), Istituto di Ricerca Pediatrica Città della Speranza (Project n. IRP18/06) (to LP) and the Italian Association for Cancer Research (AIRC, IG-17035 and Special Program Molecular Clinical Oncology 5 per mille ID 10016) (to AR).

EP was supported by a fellowship from AIRC (n.14978 and n.16601) and from Umberto Veronesi Foundation (FUV, n.1142). FM is supported by a fellowship from AIRC (n.19575).

Author contributions:

Conceived and designed the experiments: EP, LP. Performed the experiments: EP, FM, DB, ER, VB, CF, GZ. Analyzed the data: EP, LP, GZ, GV. Contributed reagents/materials/ analysis tools: ADP, AR, GB. Wrote/revised the paper: LP, EP, GB, AR, GV.

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Author notes

  1. These authors contributed equally: Giuseppe Basso, Luca Persano.

Affiliations

  1. Department of Woman and Children Health, University of Padova, Padova, Italy

    • Elena Porcù
    • , Francesca Maule
    • , Daniele Boso
    • , Elena Rampazzo
    • , Chiara Frasson
    • , Giampietro Viola
    •  & Giuseppe Basso
  2. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

    • Vito Barbieri
    • , Gaia Zuccolotto
    •  & Antonio Rosato
  3. Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy

    • Vito Barbieri
    •  & Antonio Rosato
  4. Istituto di Ricerca Pediatrica - Città della Speranza – IRP, Padova, Italy

    • Chiara Frasson
    •  & Luca Persano
  5. Neurosurgery Unit, Padova University Hospital, Padova, Italy

    • Alessandro Della Puppa

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The authors declare that they have no conflict of interest.

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Correspondence to Luca Persano.

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DOI

https://doi.org/10.1038/s41418-018-0149-9

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Edited by RA Knight

Article notes

These authors contributed equally: Giuseppe Basso, Luca Persano.