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

Elena Pagani, Federica Ruffini, Gian Carlo Antonini Cappellini, Alessandro Scoppola, Cristina Fortes, Paolo Marchetti, Grazia Graziani, Stefania D'Atri, Pedro Miguel Lacal

Research output: Contribution to journalArticlepeer-review


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 proangiogenic mechanism that may contribute to the resistance to therapies targeting VEGF-A.

Original languageEnglish
Pages (from-to)1581-1589
Number of pages9
JournalInternational Journal of Oncology
Issue number4
Publication statusPublished - Apr 1 2016


  • bevacizumab
  • melanoma
  • neuropilin-1
  • PlGF
  • vasculogenic mimicry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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