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Am J Physiol Heart Circ Physiol 284: H317-H329, 2003. First published September 19, 2002; doi:10.1152/ajpheart.00971.2001
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Vol. 284, Issue 1, H317-H329, January 2003

TNF-alpha downregulates vascular endothelial Flk-1 expression in human melanoma xenograft model

Chandrakala Menon, Malini Iyer, Indira Prabakaran, Robert J. Canter, Shannon C. Lehr, and Douglas L. Fraker

Harrison Department of Surgical Research, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

High-dose TNF with melphalan has significant antitumor activity in regional perfusion of the limbs and liver in human malignancies. TNF is believed to target tumor vasculature, but the precise molecular mechanism is unknown. The present study demonstrates that TNF downregulates the VEGF receptor, fetal liver kinase-1 (Flk-1), on tumor endothelium in a human melanoma xenograft model. NIH1286 human melanoma cells were transduced with a 720-bp fragment of the human VEGF121 gene to develop well-vascularized tumors that served as an amplified system for measuring Flk-1 expression changes. We injected 5 × 106 cells subcutaneously, each of two distinct single cell clones (NIH1286/3 and NIH1286/15), into athymic nude mice to produce tumors ~10 mm in size. Each animal then received either BSA or TNF in BSA by tail vein. Tumors harvested at different time points post-TNF were analyzed for Flk-1 mRNA and protein expression. Data obtained showed that intravascular TNF downregulated Flk-1 expression in tumor endothelial cells. This effect could contribute to the antitumor activity of TNF known to target tumor vasculature.

vascular endothelial growth factor receptor; antitumor therapy; antiangiogenic therapy; antivascular therapy


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