Downregulation of vascular endothelial-cadherin expression is associated with an increase in vascular tumor growth and hemorrhagic complications.
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.
Zanetta
Lucia
L
FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
Corada
Monica
M
Grazia Lampugnani
Maria
M
Zanetti
Adriana
A
Breviario
Ferruccio
F
Moons
Lieve
L
Carmeliet
Peter
P
Pepper
Michael S
MS
Dejana
Elisabetta
E
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
D015703:Antigens, CD; D015820:Cadherins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D000099152:Cadherin 5