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.
Pagani, E., Ruffini, F., Cappellini, G., Scoppola, A., Fortes, C., Marchetti, P., et al. (2016). Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness. INTERNATIONAL JOURNAL OF ONCOLOGY, 48(4), 1581-1589 [10.3892/ijo.2016.3362].
|Tipologia:||Articolo su rivista|
|Citazione:||Pagani, E., Ruffini, F., Cappellini, G., Scoppola, A., Fortes, C., Marchetti, P., et al. (2016). Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness. INTERNATIONAL JOURNAL OF ONCOLOGY, 48(4), 1581-1589 [10.3892/ijo.2016.3362].|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore BIO/14|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3892/ijo.2016.3362|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2016|
|Titolo:||Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness|
|Autori:||Pagani, E; Ruffini, F; Cappellini, Gca; Scoppola, A; Fortes, C; Marchetti, P; Graziani, G; D'Atri, S; Lacal, Pm|
|Appare nelle tipologie:||01 - Articolo su rivista|