Induction of endothelial nitric oxide synthase expression by melanoma sensitizes endothelial cells to tumor necrosis factor-driven cytotoxicity

Simone Mocellin, Maurizio Provenzano, Carlo Riccardo Rossi, Pierluigi Pilati, Romano Scalerta, Mario Lise, Donato Nitti

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: The cascade of molecular events leading to tumor necrosis factor (TNF)-mediated tumor regression is still incompletely elucidated. We investigated the role of endothelial nitric oxide synthase in determining the tumor-selective activity of TNF. Experimental Design: Using quantitative real-time PCR, endothelial nitric oxide synthase gene levels were measured in melanoma metastases of the skin and normal skin biopsies obtained from 12 patients before undergoing TNF-based therapy. In vitro, the ability of melanoma cells supernatant to affect endothelial nitric oxide synthase transcription by endothelial cells and the influence of nitric oxide synthase inhibition on TNF cytotoxicity toward endothelial cells was evaluated. Results: Endothelial nitric oxide synthase transcript abundance resulted significantly greater in tumor samples rather than in normal skin samples and in patients showing complete response to TNF-based treatment rather than in those showing partial/minimal response. In vitro, melanoma cells' supernatant induced endothelial nitric oxide synthase gene expression by endothelial cells. Nitric oxide synthase inhibition slowed endothelial cells proliferation and, if induced before TNF administration, decreased the cytokine-mediated cytotoxicity on endothelial cells. Conclusions: Taken together, these findings support the hypothesis that high expression of endothelial nitric oxide synthase in the tumor microenvironment might increase or be a marker for endothelial cells sensitivity to TNF. These observations may have important prognostic and/or therapeutic implications in the clinical setting.

Original languageEnglish
Pages (from-to)6879-6886
Number of pages8
JournalClinical Cancer Research
Volume10
Issue number20
DOIs
Publication statusPublished - Oct 15 2004

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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