Tumor necrosis factor-alpha damages tumor blood vessel integrity by targeting VE-cadherin |
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Authors: | Menon Chandrakala Ghartey Antoinette Canter Robert Feldman Michael Fraker Douglas L |
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Institution: | Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA. |
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Abstract: | BACKGROUND: Isolated limb perfusion using high-dose human tumor necrosis factor-alpha with melphalan is effective therapy for bulky extremity in-transit melanoma and sarcoma. OBJECTIVE: While it is widely accepted that melphalan is a DNA alkylating agent, the mechanism of selective antitumor effect of tumor necrosis factor-alpha is unclear. METHODS AND RESULTS: Electron microscopic analyses of human melanoma biopsies, pre- and post-melphalan perfusion, showed that the addition of tumor necrosis factor-alpha caused gapping between endothelial cells by 3 to 6 hours post-treatment followed by vascular erythrostasis in treated tumors. In human melanoma xenografts raised in mice, tumor necrosis factor-alpha selectively increased tumor vascular permeability by 3 hours and decreased tumor blood flow by 6 hours post-treatment relative to treated normal tissue. In an in vitro tumor endothelial cell model, tumor necrosis factor-alpha caused vascular endothelial adherens junction protein, VE-cadherin, to relocalize within the cell membrane away from cell-cell junctions leading to gapping between endothelial cells by 3 to 6 hours post-treatment. Phosphotyrosinylation was a prerequisite for movement of VE-cadherin away from endothelial cell junctions and for gapping between endothelial cells. Clinical isolated limb perfusion tumor specimens, at 3 hours postperfusion, showed a discontinuous and irregular pattern of VE-cadherin expression at endothelial cell junctions when compared with normal (skin) or pretreatment tumor tissue. CONCLUSIONS: Together, the data suggest that tumor necrosis factor-alpha selectively damages the integrity of tumor vasculature by disrupting VE-cadherin complexes at vascular endothelial cell junctions leading to gapping between endothelial cells, causing increased vascular leak and erythrostasis in tumors. VE-cadherin appears to be a potentially good target for selective antitumor therapy. |
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