title: Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness.
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.
authors: Laboratory of Molecular Oncology, 'Istituto Dermopatico dell'Immacolata'- IRCCS, Rome, Italy.
authors: Elena
authors: E
authors: Pagani
authors: Laboratory of Molecular Oncology, 'Istituto Dermopatico dell'Immacolata'- IRCCS, Rome, Italy.
authors: Federica
authors: F
authors: Ruffini
authors: Department of Oncology and Dermatological Oncology, 'Istituto Dermopatico dell'Immacolata'- IRCCS, Rome, Italy.
authors: Gian Carlo
authors: GC
authors: Antonini Cappellini
authors: Department of Oncology and Dermatological Oncology, 'Istituto Dermopatico dell'Immacolata'- IRCCS, Rome, Italy.
authors: Alessandro
authors: A
authors: Scoppola
authors: Epidemiology Unit, 'Istituto Dermopatico dell'Immacolata'- IRCCS, Rome, Italy.
authors: Cristina
authors: C
authors: Fortes
authors: Department of Oncology, Sant'Andrea Hospital, University of Rome 'La Sapienza', Rome, Italy.
authors: Paolo
authors: P
authors: Marchetti
authors: Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
authors: Grazia
authors: G
authors: Graziani
authors: Laboratory of Molecular Oncology, 'Istituto Dermopatico dell'Immacolata'- IRCCS, Rome, Italy.
authors: Stefania
authors: S
authors: D'Atri
authors: Laboratory of Molecular Oncology, 'Istituto Dermopatico dell'Immacolata'- IRCCS, Rome, Italy.
authors: Pedro Miguel
authors: PM
authors: Lacal
mesh_terms: D000328:Adult; D000368:Aged; D000068258:Bevacizumab / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D039942:Neuropilin-1 / Q000378:metabolism*; D000072483:Placenta Growth Factor / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D055815:Young Adult
chemical_list: C000608036:PGF protein, human; D000072483:Placenta Growth Factor; D039942:Neuropilin-1; D000068258:Bevacizumab; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1