['Osteosarcoma is the most common primary bone malignancy and accounts for more than half of primary skeletal malignancies in children and young adults. Although vascular endothelial growth factor (VEGF) expression in osteosarcoma has been associated with poor outcome, its role in the pathogenesis of osteosarcoma remains controversial. Here, VEGF and VEGFR1 expression in both human and murine osteosarcoma cells associated with increasing malignant potential. Autocrine VEGF/VEGFR1 signaling resulted in constitutive activation of VEGFR1 in highly aggressive osteosarcoma cells. In addition, survival and proliferation of highly aggressive osteosarcoma cells was dependent on autocrine VEGF/R1 signaling in vitro. The effect of VEGFR1 expression on in vivo tumor growth and angiogenesis was evaluated by immunoselecting subpopulations of osteosarcoma cells that express high or low levels of VEGFR1. Cell enriched for high VEGFR1 expression showed increased VEGF production, tumor growth, tumor angiogenesis, and osteolysis in vivo. In addition, it was demonstrated that VEGF and VEGFR1 are coexpressed by a subset of tumor cells in human osteosarcoma, similar to what was observed in the murine osteosarcoma cells. These results suggest that autocrine VEGF/VEGFR1 signaling in a subpopulation of tumor cells plays a pivotal role in osteosarcoma progression.'] Does autocrine VEGF/VEGFR1 signaling in a subpopulation of cells associate with aggressive osteosarcoma?