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(American Journal of Pathology. 2000;156:1469-1476.)
© 2000 American Society for Investigative Pathology

Animal Models

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

Jack L. Arbiser^*, Helena Larsson^¶, Lena Claesson-Welsh^¶, Xianhe Bai^*, Kenneth LaMontagne, Sharon W. Weiss, Shai Soker, Evelyn Flynn and Lawrence F. Brown^§

From the Departments of Dermatology^*
and Pathology,
Emory University School of Medicine, Atlanta, Georgia; the Department of Surgery,
Children’s Hospital, Harvard Medical School, Boston, Massachusetts; the Department of Pathology,^§
Beth Israel Deaconness Medical Center, Harvard Medical School, Boston, Massachusetts; and the Department of Genetics and Pathology,^¶
Rudbeck Laboratory Uppsala University, Uppsala, Sweden

Vascular endothelial growth factor (VEGF or vascular permeability factor) is an important angiogenic factor that is up-regulated in numerous benign and malignant disorders, including angiosarcoma, hemangiomas, and solid tumors. To determine the functional role of VEGF in the development of endothelial tumors, we expressed primate VEGF 121 in an endothelial cell line, MS1, derived from primary murine cells by immortalization with a temperature-sensitive SV40 large T antigen. This cell line expresses the VEGFR-2 (Flk-1/Kdr) receptor for VEGF. Expression of VEGF 121 led to the development of slowly growing endothelial tumors, which were histologically well-differentiated angiosarcomas. The angiosarcomas generated from MS1 VEGF cells demonstrated 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 these cells with the VEGFR-2 tyrosine kinase inhibitor SU 1498 led to decreased expression of ets-1, a transcription factor which has been shown to be stimulated by VEGF. These results suggest that high level expression of VEGF in endothelial cells may result in malignant transformation. This transformation process likely involves both autocrine and paracrine pathways.

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