title: Tumor necrosis factor-alpha damages tumor blood vessel integrity by targeting VE-cadherin.
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.
  
  
  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.
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Menon
authors.forename: Antoinette
authors.initials: A
authors.lastname: Ghartey
authors.forename: Robert
authors.initials: R
authors.lastname: Canter
authors.forename: Michael
authors.initials: M
authors.lastname: Feldman
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Fraker
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism*; D001706:Biopsy; D001783:Blood Flow Velocity; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005434:Flow Cytometry; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D009368:Neoplasm Transplantation; D012867:Skin / Q000098:blood supply* / Q000503:physiopathology / Q000648:ultrastructure; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D014409:Tumor Necrosis Factor-alpha; D000099152:Cadherin 5