Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

Tumor Necrosis Factor-alpha Damages Tumor Blood Vessel Integrity by Targeting VE-Cadherin

Menon, Chandrakala MSc, PhD*; Ghartey, Antoinette BA*; Canter, Robert MD*; Feldman, Michael MD, PhD; Fraker, Douglas L. MD*

doi: 10.1097/01.sla.0000231723.81218.72
Original Articles
Buy

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.

Isolated limb perfusion with high-dose tumor necrosis factor-alpha (TNF) plus melphalan is effective therapy for bulky extremity in-transit melanoma and sarcoma. TNF selectively damages the integrity of tumor vasculature by phosphorylating vascular endothelial-cadherin (VE-cadherin), resulting in gapping between endothelial cells leading to increased vascular leak and erythrostasis.

From the *Division of Endocrine and Oncologic Surgery, Department of Surgery and †Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.

Supported in part by the Georgene S. Harmelin Endowment Fund (to D.L.F.).

Reprints: Douglas Fraker, MD, Division of Endocrine and Oncologic Surgery, University of Pennsylvania, 4th Floor, Silverstein Building, 3400 Spruce Street, Philadelphia, PA 19104. E-mail: Frakerd@uphs.upenn.edu.

© 2006 Lippincott Williams & Wilkins, Inc.