uPAR mediates anticancer activity of PEDF

Abstract

Osteosarcoma (OS) is a cancer which afflicts the bone, ending in usually fatal lung metastasis mainly in teenagers and adolescents. We have recently shown that PEDF is one biological that has multiple anti-OS activity. In parallel, we have also shown using rodent cells, the beneficial effects of downregulation of uPAR against OS. Here, we provide further proof of such effects of uPAR downregulation using human OS cells and combine this with PEDF treatment. We describe the involvement of uPAR with activity of PEDF. In silico, PEDF did not bind to uPA and thus did not attenuate its activity. In the presence of exogenous PEDF, both uPA, its receptor and FAK localize intracellularly. Blocking of uPA and uPAR on the cell surface increased the binding of PEDF, whether endogenous or exogenous. In clinical specimens of OS, there was mutually exclusive expression of PEDF and uPAR at the growing edge of the tumor. Incubation of cells with PEDF and a uPAR antibody led to an increased reduction in invasion of cells through Matrigel, and a heightened apoptotic signal. In vivo, treatment of human OS cells with both PEDF and uPAR DNAzyme resulted in greater primary tumor growth, pulmonary metastasis inhibition and decreased osteolysis. Areas of necrosis were noted in the PEDF-administered group of animals. This study shows an association between two very important systems involved in tumor progression and highlights the possibility that a combined approach of PEDF exposure and uPAR knockdown may lead to a better targeted outcome against OS.