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

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

doi:10.3892/ijo.2016.3362

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

Affiliations: Laboratory of Molecular Oncology, ‘Istituto Dermopatico dell'Immacolata’- IRCCS, Rome, Italy, Department of Oncology and Dermatological Oncology, ‘Istituto Dermopatico dell'Immacolata’- IRCCS, Rome, Italy, Epidemiology Unit, ‘Istituto Dermopatico dell'Immacolata’- IRCCS, Rome, Italy, Department of Oncology, Sant'Andrea Hospital, University of Rome ‘La Sapienza’, Rome, Italy, Department of Systems Medicine, University of Rome ‘Tor Vergata’, Rome, Italy
Published online on: January 29, 2016 https://doi.org/10.3892/ijo.2016.3362
Pages: 1581-1589

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Fischer C, Mazzone M, Jonckx B and Carmeliet P: FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer. 8:942–956. 2008. View Article : Google Scholar : PubMed/NCBI
2	Roskoski R Jr: VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Biophys Res Commun. 375:287–291. 2008. View Article : Google Scholar : PubMed/NCBI
3	Lohela M, Bry M, Tammela T and Alitalo K: VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 21:154–165. 2009. View Article : Google Scholar : PubMed/NCBI
4	Dewerchin M and Carmeliet P: Placental growth factor in cancer. Expert Opin Ther Targets. 18:1339–1354. 2014. View Article : Google Scholar : PubMed/NCBI
5	Kim KJ, Cho CS and Kim WU: Role of placenta growth factor in cancer and inflammation. Exp Mol Med. 44:10–19. 2012. View Article : Google Scholar : PubMed/NCBI
6	Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, et al: Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med. 9:936–943. 2003. View Article : Google Scholar : PubMed/NCBI
7	Marcellini M, De Luca N, Riccioni T, Ciucci A, Orecchia A, Lacal PM, Ruffini F, Pesce M, Cianfarani F, Zambruno G, et al: Increased melanoma growth and metastasis spreading in mice overexpressing placenta growth factor. Am J Pathol. 169:643–654. 2006. View Article : Google Scholar : PubMed/NCBI
8	Levati L, Ruffini F, Muzi A, Umezawa K, Graziani G, D'Atri S and Lacal PM: Placenta growth factor induces melanoma resistance to temozolomide through a mechanism that involves the activation of the transcription factor NF-κB. Int J Oncol. 38:241–247. 2011.
9	Schwartz JD, Rowinsky EK, Youssoufian H, Pytowski B and Wu Y: Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1). Cancer. 116(Suppl): 1027–1032. 2010. View Article : Google Scholar : PubMed/NCBI
10	Adini A, Kornaga T, Firoozbakht F and Benjamin LE: Placental growth factor is a survival factor for tumor endothelial cells and macrophages. Cancer Res. 62:2749–2752. 2002.PubMed/NCBI
11	Zhou Y, Bellingard V, Feng K-T, McMaster M and Fisher SJ: Human cytotrophoblasts promote endothelial survival and vascular remodeling through secretion of Ang2, PlGF, and VEGF-C. Dev Biol. 263:114–125. 2003. View Article : Google Scholar : PubMed/NCBI
12	Wu Y, Hooper AT, Zhong Z, Witte L, Bohlen P, Rafii S and Hicklin DJ: The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int J Cancer. 119:1519–1529. 2006. View Article : Google Scholar : PubMed/NCBI
13	Wu Y, Zhong Z, Huber J, Bassi R, Finnerty B, Corcoran E, Li H, Navarro E, Balderes P, Jimenez X, et al: Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin Cancer Res. 12:6573–6584. 2006. View Article : Google Scholar : PubMed/NCBI
14	Fragoso R, Pereira T, Wu Y, Zhu Z, Cabeçadas J and Dias S: VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease. Blood. 107:1608–1616. 2006. View Article : Google Scholar
15	Lacal PM, Failla CM, Pagani E, Odorisio T, Schietroma C, Falcinelli S, Zambruno G and D'Atri S: Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. J Invest Dermatol. 115:1000–1007. 2000. View Article : Google Scholar : PubMed/NCBI
16	Graells J, Vinyals A, Figueras A, Llorens A, Moreno A, Marcoval J, Gonzalez FJ and Fabra A: Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling. J Invest Dermatol. 123:1151–1161. 2004. View Article : Google Scholar : PubMed/NCBI
17	Graeven U, Fiedler W, Karpinski S, Ergün S, Kilic N, Rodeck U, Schmiegel W and Hossfeld DK: Melanoma-associated expression of vascular endothelial growth factor and its receptors FLT-1 and KDR. J Cancer Res Clin Oncol. 125:621–629. 1999. View Article : Google Scholar : PubMed/NCBI
18	Lacal PM, Ruffini F, Pagani E and D'Atri S: An autocrine loop directed by the vascular endothelial growth factor promotes invasiveness of human melanoma cells. Int J Oncol. 27:1625–1632. 2005.PubMed/NCBI
19	Grünewald FS, Prota AE, Giese A and Ballmer-Hofer K: Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim Biophys Acta. 1804:567–580. 2010. View Article : Google Scholar
20	Neagoe PE, Lemieux C and Sirois MG: Vascular endothelial growth factor (VEGF)-A165-induced prostacyclin synthesis requires the activation of VEGF receptor-1 and -2 heterodimer. J Biol Chem. 280:9904–9912. 2005. View Article : Google Scholar : PubMed/NCBI
21	Allain B, Jarray R, Borriello L, Leforban B, Dufour S, Liu WQ, Pamonsinlapatham P, Bianco S, Larghero J, Hadj-Slimane R, et al: Neuropilin-1 regulates a new VEGF-induced gene, Phactr-1, which controls tubulogenesis and modulates lamel-lipodial dynamics in human endothelial cells. Cell Signal. 24:214–223. 2012. View Article : Google Scholar
22	Chittenden TW, Claes F, Lanahan AA, Autiero M, Palac RT, Tkachenko EV, Elfenbein A, Ruiz de Almodovar C, Dedkov E, Tomanek R, et al: Selective regulation of arterial branching morphogenesis by synectin. Dev Cell. 10:783–795. 2006. View Article : Google Scholar : PubMed/NCBI
23	Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W, et al: Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell. 152:1065–1076. 2013. View Article : Google Scholar : PubMed/NCBI
24	Ellis LM: The role of neuropilins in cancer. Mol Cancer Ther. 5:1099–1107. 2006. View Article : Google Scholar : PubMed/NCBI
25	Holmes K, Roberts OL, Thomas AM and Cross MJ: Vascular endothelial growth factor receptor-2: structure, function, intra-cellular signalling and therapeutic inhibition. Cell Signal. 19:2003–2012. 2007. View Article : Google Scholar : PubMed/NCBI
26	van Beijnum JR, Nowak-Sliwinska P, Huijbers EJ, Thijssen VL and Griffioen AW: The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol Rev. 67:441–461. 2015. View Article : Google Scholar : PubMed/NCBI
27	Lambrechts D, Lenz HJ, de Haas S, Carmeliet P and Scherer SJ: Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. 31:1219–1230. 2013. View Article : Google Scholar : PubMed/NCBI
28	Ruffini F, D'Atri S and Lacal PM: Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms. Int J Oncol. 43:297–306. 2013.PubMed/NCBI
29	Ruffini F, Graziani G, Levati L, Tentori L, D'Atri S and Lacal PM: Cilengitide downmodulates invasiveness and vasculogenic mimicry of neuropilin 1 expressing melanoma cells through the inhibition of αvβ5 integrin. Int J Cancer. 136:E545–E558. 2015. View Article : Google Scholar
30	Orecchia A, Lacal PM, Schietroma C, Morea V, Zambruno G and Failla CM: Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the alpha 5 beta 1 integrin. J Cell Sci. 116:3479–3489. 2003. View Article : Google Scholar : PubMed/NCBI
31	Ruffini F, Tentori L, Dorio AS, Arcelli D, D'Amati G, D'Atri S, Graziani G and Lacal PM: Platelet-derived growth factor C and calpain-3 are modulators of human melanoma cell invasiveness. Oncol Rep. 30:2887–2896. 2013.PubMed/NCBI
32	Seftor RE, Hess AR, Seftor EA, Kirschmann DA, Hardy KM, Margaryan NV and Hendrix MJ: Tumor cell vasculogenic mimicry: From controversy to therapeutic promise. Am J Pathol. 181:1115–1125. 2012. View Article : Google Scholar : PubMed/NCBI
33	Escudero-Esparza A, Martin TA, Douglas-Jones A, Mansel RE and Jiang WG: PGF isoforms, PLGF-1 and PGF-2 and the PGF receptor, neuropilin, in human breast cancer: prognostic significance. Oncol Rep. 23:537–544. 2010.PubMed/NCBI
34	Banerjee S, Sengupta K, Dhar K, Mehta S, D'Amore PA, Dhar G and Banerjee SK: Breast cancer cells secreted platelet-derived growth factor-induced motility of vascular smooth muscle cells is mediated through neuropilin-1. Mol Carcinog. 45:871–880. 2006. View Article : Google Scholar : PubMed/NCBI
35	Dhar K, Dhar G, Majumder M, Haque I, Mehta S, Van Veldhuizen PJ, Banerjee SK and Banerjee S: Tumor cell-derived PDGF-B potentiates mouse mesenchymal stem cells-pericytes transition and recruitment through an interaction with NRP-1. Mol Cancer. 9:2092010. View Article : Google Scholar : PubMed/NCBI
36	Pellet-Many C, Frankel P, Evans IM, Herzog B, Jünemann-Ramírez M and Zachary IC: Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas. Biochem J. 435:609–618. 2011. View Article : Google Scholar : PubMed/NCBI
37	Frank A, David V, Aurelie TR, Florent G, William H and Philippe B: Regulation of MMPs during melanoma progression: from genetic to epigenetic. Anticancer Agents Med Chem. 12:773–782. 2012. View Article : Google Scholar : PubMed/NCBI
38	Tamiya M, Tamiya A, Yamadori T, Nakao K, Asami K, Yasue T, Otsuka T, Shiroyama T, Morishita N, Suzuki H, et al: Phase2 study of bevacizumab with carboplatin-paclitaxel for non-small cell lung cancer with malignant pleural effusion. Med Oncol. 30:6762013. View Article : Google Scholar : PubMed/NCBI
39	Jayasinghe C, Simiantonaki N and Kirkpatrick CJ: Cell type- and tumor zone-specific expression of pVEGFR-1 and its ligands influence colon cancer metastasis. BMC Cancer. 15:1042015. View Article : Google Scholar : PubMed/NCBI
40	Bagley RG, Ren Y, Weber W, Yao M, Kurtzberg L, Pinckney J, Bangari D, Nguyen C, Brondyk W, Kaplan J, et al: Placental growth factor upregulation is a host response to antiangiogenic therapy. Clin Cancer Res. 17:976–988. 2011. View Article : Google Scholar : PubMed/NCBI
41	Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, et al: Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 131:463–475. 2007. View Article : Google Scholar : PubMed/NCBI
42	Liang WC, Dennis MS, Stawicki S, Chanthery Y, Pan Q, Chen Y, Eigenbrot C, Yin J, Koch AW, Wu X, et al: Function blocking antibodies to neuropilin-1 generated from a designed human synthetic antibody phage library. J Mol Biol. 366:815–829. 2007. View Article : Google Scholar : PubMed/NCBI
43	Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N, Tong RK, Kowalski J, Yee SF, Pacheco G, et al: Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell. 11:53–67. 2007. View Article : Google Scholar : PubMed/NCBI
44	Xin Y, Li J, Wu J, Kinard R, Weekes CD, Patnaik A, Lorusso P, Brachmann R, Tong RK, Yan Y, et al: Pharmacokinetic and pharmacodynamic analysis of circulating biomarkers of anti-NRP1, a novel antiangiogenesis agent, in two phase I trials in patients with advanced solid tumors. Clin Cancer Res. 18:6040–6048. 2012. View Article : Google Scholar : PubMed/NCBI
45	Jia H, Cheng L, Tickner M, Bagherzadeh A, Selwood D and Zachary I: Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity. Br J Cancer. 102:541–552. 2010. View Article : Google Scholar : PubMed/NCBI
46	Zeng F, Luo F, Lv S, Zhang H, Cao C, Chen X, Wang S, Li Z, Wang X, Dou X, et al: A monoclonal antibody targeting neuropilin-1 inhibits adhesion of MCF7 breast cancer cells to fibronectin by suppressing the FAK/p130cas signaling pathway. Anticancer Drugs. 25:663–672. 2014.PubMed/NCBI
47	Graziani G and Lacal PM: Neuropilin-1 as therapeutic target for malignant melanoma. Front Oncol. 5:1252015. View Article : Google Scholar : PubMed/NCBI