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, Table of Contents

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

Authors

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

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

Full Text

References

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