The urokinase receptor-derived cyclic peptide [SRSRY] suppresses neovascularization and intravasation of osteosarcoma and chondrosarcoma cells

// Vincenzo Ingangi 1, 2 , Katia Bifulco 1 , Ali Munaim Yousif 3 , Concetta Ragone 1, 2 , Maria Letizia Motti 4 , Domenica Rea 5 , Michele Minopoli 1 , Giovanni Botti 1 , Giuseppe Scognamiglio 6 , Flavio Fazioli 7 , Michele Gallo 7 , Annarosaria De Chiara 6 , Claudio Arra 5 , Paolo Grieco 3 , Maria Vincenza Carriero 1 1 Neoplastic Progression Unit, Department of Experimental Oncology, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy 2 SUN Second University of Naples, Naples, Italy 3 Department of Pharmacy, University Federico II, Naples, Italy 4 University ‘Parthenope’, Naples, Italy 5 Animal Facility, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy 6 Pathology Unit, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy 7 Surgery Unit, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy Correspondence to: Maria Vincenza Carriero, email: mariolinacarriero@yahoo.it , m.carriero@istitutotumori.na.it Keywords: urokinase receptor, formyl peptide receptor type 1, osteosarcoma, chondrosarcoma, peptides Received: April 18, 2016      Accepted: May 20, 2016      Published: June 13, 2016 ABSTRACT The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR 88–92 is the minimal sequence required to induce cell motility and angiogenesis by interacting with the formyl peptide receptor type 1 (FPR1). In this study, we present evidence that the cyclization of the uPAR 88–92 sequence generates a new potent inhibitor of migration, and extracellular matrix invasion of human osteosarcoma and chondrosarcoma cells expressing comparable levels of FPR1 on cell surface. In vitro , the cyclized peptide [SRSRY] prevents formation of capillary-like tubes by endothelial cells co-cultured with chondrosarcoma cells and trans-endothelial migration of osteosarcoma and chondrosarcoma cells. When chondrosarcoma cells were subcutaneously injected in nude mice, tumor size, intra-tumoral microvessel density and circulating tumor cells in blood samples collected before the sacrifice, were significantly reduced in animals treated daily with i.p-administration of 6 mg/Kg [SRSRY] as compared to animals treated with vehicle only. Our findings indicate that [SRSRY] prevents three key events occurring during the metastatic process of osteosarcoma and chondrosarcoma cells: the extracellular matrix invasion, the formation of a capillary network and the entry into bloodstream.