caveolin-1 acts as an oncosuppressor in osteosarcoma by inhibiting c-src and Met signalling

3675 In this study, we show that down-regulation of Caveolin-1 (Cav-1) is required for osteosarcoma pathogenesis and progression. Cav-1, which is highly expressed in normal osteoblasts, is downregulated following Met induced osteoblasts transformation. Accordingly, osteosarcoma primary tumors have significantly lower levels of Cav-1 than normal osteoblasts. When the expression of Cav-1 in osteosarcoma is similar to that of normal osteoblasts, patients overall, but not event-free, survival at 6 ys follow-up outcome was remarkably better. No differences in chemosensitivity to doxorubicin were observed in cells deprived or abundant of Cav-1. On the contrary, overexpression of Cav-1 greatly inhibited anchorage-independent growth, migration, invasion, while promoted adhesion to ECM components. Abrogation of metastases was recorded in cells reach of Cav-1, supporting the view of Cav-1 as a tumor suppressor gene in osteosarcomas. The oncosuppressor role of Cav-1 may pass through the modulation of c-Src family tyrosine kinase activity as well as Met signalling. Both the c-Src and Met co-localize with caveolin-1 and the related signalling pathways appeared reduced in cells with high expression of Cav-1. As a consequence, targeted therapies against c-Src family kinases and/or Met receptor may have attractive rationale to improve the extremely poor prognosis of metastatic osteosarcoma.