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

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

• References

• 1 Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982; 69: 412-22.
• 2 Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med 1999; 341: 173-81.
• 3 Vikkula M, Boon LM, Mulliken JB. Molecular genetics of vascular malformations. Matrix Biol 2001; 20: 327-35.
• 4 Takeichi M. Cadherin in cancer: implications for invasion and metastasis. Curr Opin Cell Biol 1993; 5: 806-11.
• 5 Clevers H. Inflating cell numbers by Wnt. Mol Cell 2002; 10: 1260-1.
• 6 Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: organization, intracellular signaling and functional role in maintaining vascular homeostasis. Physiol Rev 2004; Jul 84: 869-901.
• 7 Martin-Padura I, De Castellarnau C, Uccini S. et al. Expression of VE (vascular endothelial)-cadherin and other endothelial-specific markers in haemangiomas. J Pathol 1995; 175: 51-7.
• 8 Pepper MS, Tacchini-Cottier F, Uccini S. et al. Endothelial cells transformed by polymavirus middle T oncongene; a model for hemangiomas and other vascular tumors. In: Tumor Angiogenesis. Bicknell R, Lewis CE. 1997. Ferrara N; Oxford University Press:
• 9 Carmeliet P, Lampugnani MG, Moons L. et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 1999; 98: 147-57.
• 10 Lampugnani MG, Zanetti A, Breviario F. et al. VEcadherin regulates endothelial actin activating Rac and increasing membrane association of Tiam. Mol Biol Cell 2002; 13: 1175-89.
• 11 Lampugnani MG, Zanetti A, Corada M. et al. Contact inhibition of VEGF-induced proliferation requires VE-cadherin, b-catenin and the phosphatase DEP- 1/CD148. J Cell Biol 2003; 161: 793-804.
• 12 Morgenstern JP, Land H.. et al. Advanced mammalian gene transfer: high titre retroviral vectors with multipledrug selection markers and a complementary helperfree packaging cell line. Nucleic Acids Res 1990; 18: 3587-96. june
• 13 Corada M, Thurston G, Lindgren M. et al. Vascular Endothelial-cadherin is an important determinant of microvascular integrity in vivo Proc Natl Acad Sci USA. 1999; 96: 9815-20.
• 14 Corada M, Liao F, Lindgren M. et al. Monoclonal antibodies directed to different regions of vascular endothelial cadherin extracellular domain affect adhesion and clustering of the protein and modulate endothelial permeability. Blood 2001; 97: 1679-84.
• 15 Liao F, Li Y, O'Connor W. et al. Monoclonal antibody to vascular endothelial-cadherin is a potent inhibitor of angiogenesis, tumor growth, and metastasis. Cancer Res 2000; 60: 6805-10. Dec 15
• 16 Lu C, Schwartzbauer G, Sperling MA. et al. Demonstration of direct effects of growth hormone on neonatal cardiomyocytes. J Biol Chem 2001; 276: 22892-900.
• 17 Pepper MS, Belin D, Montesano R. et al. Upregulation of urokinase receptor expression on migrating endothelial cells. J Cell Biol 1993; 122: 673-84.
• 18 Sabapathy KT, Pepper MS, Kiefer F. et al. Polyoma middle T-induced vascular tumor formation: the role of the plasminogen activator/plasmin system. J Cell Biol 1997; 137: 953-63.
• 19 Garlanda C, Parravicinir C, Sironi M. et al. Progressive growth in immunodeficient mice and host cell recruitment by mouse endothelial cells transformed by polyoma middle-sized T antigen: implications for the pathogenesis of opportunistic vascular tumors. Proc Natl Acad Sci U.S.A 1994; 91: 7291-5.
• 20 Nieman MT, Prudoff RS, Johnson KR. et al. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol 1999; 147: 631-44. Nov 1
• 21 Durand MK, Bodker JS, Christensen A. et al. Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb Haemost 2004; 91: 438-49.
• 22 Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3: 932-43.
• 23 Munshi HG, Ghosh S, Mukhopadhyay S. et al. Proteinase suppression by E-cadherin-mediated cell-cell attachment in premalignant oral keratinocytes. J Biol Chem 2002; 277: 38159-67.