title: Downregulation of vascular endothelial-cadherin expression is associated with an increase in vascular tumor growth and hemorrhagic complications.
abstract: The pathogenesis of vascular tumors such as angiosarcomas is poorly understood. Cadherin expression inversely correlates with tumor malignancy and the endothelial specific VE-cadherin is low or absent in angiosarcomas, suggesting an inhibitory role for this protein in tumor progression. In this paper we report that PmyT VE-cadherin null (VEC null) endothelial cells form larger vascular tumors in nude mice when injected subcutaneously as compared to isogenic VE-cadherin positive (VEC pos) cells. This effect requires the association of beta-catenin to VEcadherin, since a VE-cadherin mutant lacking the domain responsible for beta-catenin binding (Deltabetacat) cannot rescue the phenotype. In VEC null cells beta-catenin is phosphorylated and partly degraded. N-cadherin is increased and detected at junctions. VEC null cells also present an altered fibrinolytic activity with increases in tPA, uPA, uPAR and a strong reduction in PAI-1, which may be correlated to the high incidence of abrupt hemorrhages in VEC null tumors. Overall, these data strongly suggest that downregulation of VE-cadherin in endothelial tumors may have important consequences for tumor growth and bleeding complications.
authors.affiliation: FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Zanetta
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia Lampugnani
authors.forename: Adriana
authors.initials: A
authors.lastname: Zanetti
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Breviario
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Michael S
authors.initials: MS
authors.lastname: Pepper
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000503:physiopathology; D005342:Fibrinolysis; D006394:Hemangiosarcoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006470:Hemorrhage / Q000209:etiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D000099152:Cadherin 5