Overexpression of VEGF 121 in immortalized endothelial cells causes conversion to slowly growing angiosarcoma and high level expression of the VEGF receptors VEGFR-1 and VEGFR-2 in vivo

Vascular endothelial growth factor (VEGF or vascular permeability factor) i s an important angiogenic factor that is up-regulated in numerous benign an d malignant disorders, including angiosarcoma, hemangiomas, and solid tumor s. To determine the functional role of VEGF in the development of endotheli al tumors, we expressed primate VEGF 121 in an endothelial cell line, MS1, derived from primary murine cells by immortalization with a temperature-sen sitive SV40 large T antigen. This cell line expresses the VEGFR-2 (Flk-1/Kd r) receptor for VEGF. Expression of VEGF 121 led to the development of slow ly growing endothelial tumors, which were histologically well-differentiate d angiosarcomas. The angiosarcomas generated from MS1 VEGF cells demonstrat ed up-regulation of the VEGF receptors VEGFR-2 and VEGFR-1 (Flt-1) in vivo compared with benign hemangiomas generated from MS1 cells. Treatment of the se cells with the VEGFR-2 tyrosine kinase inhibitor SU 1498 led to decrease d expression of ets-1, a transcription factor which has been shown to be st imulated by VEGF. These results suggest that high level expression of VEGF in endothelial cells may result in malignant transformation. This transform ation process likely involves both autocrine and paracrine pathways.