Abstract
The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88–92 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 uPAR88–92 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.
Highlights
The development of metastases is a multistep process that requires active and localized extracellular proteolysis as well as the activation of a series of physiological and biochemical processes that govern the migration from the primary tumor site, the invasion through the basement membrane, the entry of metastatic cells into the blood vessels and localization to the second site
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 [Ser-Arg-Ser-Arg-Tyr peptide (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
Summary
The development of metastases is a multistep process that requires active and localized extracellular proteolysis as well as the activation of a series of physiological and biochemical processes that govern the migration from the primary tumor site, the invasion through the basement membrane, the entry of metastatic cells into the blood vessels and localization to the second site. Elucidating the mechanisms controlling metastasis is important for improving outcome of patient with osteosarcoma or chondrosarcoma Both diseases are characterized by high neovascularization and a high propensity to metastasize through bloodstream [3], www.impactjournals.com/oncotarget but the cellular processes that lead to their interactions with endothelium and subsequent invasion through endothelial environment are poorly understood. The clinical relevance of uPAR as a prognostic marker, when measured in tumor tissues and/or plasma, has been demonstrated in various cancer diseases, including sarcomas and chondrosarcomas [6,7,8]. It has been documented in a mouse model of osteosarcoma that silencing expression of uPAR results in a significant reduction of metastasis to lung [9]
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