Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness

  • Authors:
    • Elena Pagani
    • Federica Ruffini
    • Gian Carlo Antonini Cappellini
    • Alessandro Scoppola
    • Cristina Fortes
    • Paolo Marchetti
    • Grazia Graziani
    • Stefania D'Atri
    • Pedro Miguel Lacal
  • View Affiliations

  • Published online on: January 29, 2016     https://doi.org/10.3892/ijo.2016.3362
  • Pages: 1581-1589
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Abstract

The placenta growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family, which shares with VEGF-A the tyrosine kinase receptor VEGFR-1 and the co-receptor neuropilin-1 (NRP-1). In melanoma models, PlGF enhances tumour growth and neovessel formation, whereas NRP-1 promotes the metastatic process. Increased secretion of PlGF and expression of NRP-1 have also been involved in intrinsic or acquired resistance to anti‑angiogenic therapies. In this study we investigated whether PlGF and NRP-1 cooperate in promoting melanoma aggressiveness independently of VEGFR-1. For this purpose, the melanoma cell clones M14-N, expressing NRP-1 and lacking VEGFR-1, and M14-C, devoid of both receptors, were used. M14-N cells are characterized by an invasive phenotype and vasculogenic mimicry, whereas M14-C cells possess a negligible invasive capacity. The results indicated that M14-N cells secrete higher levels of PlGF than M14-C cells and that PlGF is involved in the invasion of the extracellular matrix (ECM) and vasculogenic mimicry of M14-N cells. In fact, neutralizing antibodies against PlGF reverted ECM invasion in response to PlGF and markedly reduced the formation of tubule-like structures. Moreover, M14-N cells migrated in response to PlGF and chemotaxis was specifically abrogated by anti-NRP-1 antibodies, demonstrating that PlGF directly activates NRP-1 in the absence of VEGFR-1. We also compared the levels of PlGF in the plasma of patients affected by metastatic melanoma with those of healthy donors and evaluated whether PlGF levels could be affected by a bevacizumab-containing chemotherapy regimen. Melanoma patients showed a 20-fold increase in plasma PlGF and the bevacizumab-containing regimen induced a reduction of VEGF-A and in a further increase of PlGF. In conclusion, our studies suggest that the activation of NRP-1 by PlGF directly contributes to melanoma aggressiveness and represents a potential compensatory pro-angiogenic mechanism that may contribute to the resistance to therapies targeting VEGF-A.

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Copy and paste a formatted citation
APA
Pagani, E., Ruffini, F., Antonini Cappellini, G.C., Scoppola, A., Fortes, C., Marchetti, P. ... Lacal, P.M. (2016). Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness. International Journal of Oncology, 48, 1581-1589. https://doi.org/10.3892/ijo.2016.3362
MLA
Pagani, E., Ruffini, F., Antonini Cappellini, G. C., Scoppola, A., Fortes, C., Marchetti, P., Graziani, G., D'Atri, S., Lacal, P. M."Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness". International Journal of Oncology 48.4 (2016): 1581-1589.
Chicago
Pagani, E., Ruffini, F., Antonini Cappellini, G. C., Scoppola, A., Fortes, C., Marchetti, P., Graziani, G., D'Atri, S., Lacal, P. M."Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness". International Journal of Oncology 48, no. 4 (2016): 1581-1589. https://doi.org/10.3892/ijo.2016.3362