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Am J Physiol Heart Circ Physiol (September 19, 2002). doi:10.1152/ajpheart.00971.2001
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Articles in PresS, published online ahead of print September 19, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00971.2001
Submitted on November 7, 2001
Accepted on September 6, 2002

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

Chandrakala Menon1, Malini Iyer1, Indira Prabakaran1, Robert J. Canter1, Shannon C. Lehr1, and Douglas L. Fraker1*

1 Harrsion Department of Surgical Research, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: Frakerd{at}uphs.upenn.edu.

High-dose TNF with melphalan has significant anti-tumor 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 work demonstrates that TNF downregulates VEGF receptor, 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. Five x 106 cells each of two distinct single cell clones, NIH1286/3 and NIH1286/15 were injected subcutaneously into athymic nude mice to produce tumors approximately 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 may contribute to the anti-tumor activity of TNF which is known to target tumor vasculature.




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