Downregulation of vascular endothelial-cadherin expression is associated with an increase in vascular tumor growth and hemorrhagic complications

Lucia Zanetta; Monica Corada; Maria Grazia Lampugnani; Adriana Zanetti; Ferruccio Breviario; Lieve Moons; Peter Carmeliet; Michael S. Pepper; Elisabetta Dejana

doi:10.1160/TH04-10-0680

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 93(06): 1041-1046
DOI: 10.1160/TH04-10-0680

Rapid and Short Communication

Schattauer GmbH

Downregulation of vascular endothelial-cadherin expression is associated with an increase in vascular tumor growth and hemorrhagic complications

Lucia Zanetta

¹FIRC Institute of Molecular Oncology, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

⁵Department of Biomolecular and Biotechnological Sciences, University of Milan, Milan, Italy

,

Monica Corada

¹FIRC Institute of Molecular Oncology, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

²Mario Negri Institute of Pharmacological Research, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

,

Maria Grazia Lampugnani

¹FIRC Institute of Molecular Oncology, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

²Mario Negri Institute of Pharmacological Research, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

,

Adriana Zanetti

²Mario Negri Institute of Pharmacological Research, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

,

Ferruccio Breviario

¹FIRC Institute of Molecular Oncology, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

²Mario Negri Institute of Pharmacological Research, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

,

Lieve Moons

³Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

,

Peter Carmeliet

³Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

,

Michael S. Pepper

⁴Department of Morphology, University Medical Center, Geneva, Switzerland

,

Elisabetta Dejana

¹FIRC Institute of Molecular Oncology, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

²Mario Negri Institute of Pharmacological Research, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

⁵Department of Biomolecular and Biotechnological Sciences, University of Milan, Milan, Italy

› Institutsangaben

Abstract

Summary

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 Pmy T 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 β-catenin to VE-cadherin, since a VE-cadherin mutant lacking the domain responsible for β-catenin binding (Δβcat) cannot rescue the phenotype. In VEC null cells β-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.

Keywords

VE-cadherin - fibrinolysis - PAI-1 - vascular tumors

Volltext

Referenzen

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