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

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

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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 X 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume284
Issue number1 53-1
StatePublished - Jan 1 2003
Externally publishedYes

Keywords

  • Antiangiogenic therapy
  • Antitumor therapy
  • Antivascular therapy
  • Vascular endothelial growth factor receptor

ASJC Scopus subject areas

  • Physiology

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