VEGF_(165) Promotes the Osteolytic Bone Destruction of Ewing's Sarcoma Tumors by Upregulating RANKL

摘要

The purpose of this study was to determine whether vascular endothelial growth factor-165 (VEGF_(165)) contributed to the osteolytic process in Ewing's sarcoma. VEGF_(165) induced osteoclast formation from murine bone marrow cells. Tartrate-resistant acid phosphatase (TRAP) staining demonstrated significantly fewer osteoclasts in VEGF-inhibited TC/siVEGF_(7-1), tumors compared to TC71 parental or TC/si-control tumors. Receptor activator NF-kappaB (RANKL), a critical osteoclastogenic factor, was decreased in TC/siVEGF_(7-1)., cells. Incubation of these cells with recombinant VEGF_(165) upregulated RANKL in a dose- and time-dependent manner. The induction of (RANKL) by VEGF_(165) was also demonstrated in MC3T3-E1 mouse osteoblast cells and bone marrow stromal cells. This upregulation was transcriptionally mediated by an effect on the RANKL promoter. Both VEGF and EWS/FLI-1 increased RANKL promoter activity. Taken together, these data suggest that modulation of RANKL by VEGF_(165) may be one of the mechanisms responsible for the osteolytic process induced by Ewing's sarcoma cells. VEGF_(165) may, therefore, play an important role in modulating RANKL gene expression in the bone marrow microenvironment during the metastatic process, thereby contribution to tumor induced bone lysis.