Abstract
Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma. These results implicate integrin alphaVbeta3 in the anti-vascular activity of TNF and IFN-gamma and demonstrate a new mechanism by which cytokines control cell adhesion.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Biopsy
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Cell Adhesion / drug effects
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Cell Division / drug effects
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Cell Survival / drug effects
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Cells, Cultured
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects*
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Endothelium, Vascular / physiology
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Humans
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Interferon-gamma / pharmacology*
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Interferon-gamma / therapeutic use
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Melanoma / blood supply*
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Melanoma / pathology
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Melanoma / therapy
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Neoplasm Metastasis
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Neovascularization, Pathologic / psychology
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Receptors, Vitronectin / drug effects
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Receptors, Vitronectin / physiology*
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Recombinant Proteins / pharmacology
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Tumor Necrosis Factor-alpha / pharmacology*
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Tumor Necrosis Factor-alpha / therapeutic use
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Umbilical Veins
Substances
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Receptors, Vitronectin
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Interferon-gamma