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Thromb Haemost 2008; 99(01): 133-141
DOI: 10.1055/s-0037-1608919
Endothelium and Vascular Development
Schattauer GmbH

Heparanase induces tissue factor pathway inhibitor expression and extracellular accumulation in endothelial and tumor cells

Yona Nadir
1   Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
2   Thrombosis and Hemostasis Unit, Department of Hematology, Rambam Medical Center, Haifa, Israel
,
Benjamin Brenner
2   Thrombosis and Hemostasis Unit, Department of Hematology, Rambam Medical Center, Haifa, Israel
,
Sveta Gingis-Velitski
1   Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
,
Flonia Levy-Adam
1   Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
,
Neta Ilan
1   Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
,
Eyal Zcharia
3   Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
,
Erez Nadir
4   Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel
,
Israel Vlodavsky
1   Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
› Author AffiliationsFinancial support: This work was supported by the Aventis/ISTH research fellowship award and by grants from the Israel Science Foundation (grant 549/06); National Cancer Institute, NIH (grant RO1-CA106456); the Israel Cancer Research Fund; and the Rappaport Family Institute Fund.
Further Information

Publication History

Received: 17 April 2007

Accepted after major revision: 23 November 2007

Publication Date:
15 December 2017 (online)

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Summary

Heparanase activity is implicated in cell invasion, tumor metastasis and angiogenesis. Recently, we have reported that heparanase stimulates tissue factor (TF) expression in endothelial and cancer cells, resulting in elevation of coagulation activity. We hypothesized that heparanase regulates other coagulation modulators, and examined the expression and localization of tissue factor pathway inhibitor (TFPI) following heparanase over-expression or exogenous addition. Primary human umbilical vein endothelial cells (HUVEC) and human tumor-derived cell lines were incubated with heparanase, or were stably transfected with heparanase gene-constructs, and TFPI expression and secretion were examined. Heparanase over-expression or exogenous addition stimulated TFPI expression by 2–3 folds. TFPI accumulation in the cell culture medium exceeded in magnitude the observed induction ofTFPI gene transcription reaching 5– to 6-fold increase. Extracellular accumulation of TFPI was evident already 60 min following heparanase addition, prior toTFPI protein induction, and correlated with increased coagulation activity. This effect was found to be independent of heparanase enzymatic activity and interaction with heparan-sulfate, and correlated with reduced TFPI levels on the cell surface. Data were verified in heparanase transgenic mice tissues and plasma. Interaction between heparanase and TFPI was evident by co-immunoprecipitation. Interaction of heparanase with TFPI resulted in its displacement from the surface of the vascular endothelium and in increased pro-coagulant activity. Thus, heparanase facilitates blood coagulation on the cell surface by two independent mechanisms:dissociation ofTFPI from the vascular surface short after local elevation of heparanase levels, and subsequent induction of TF expression.

Keywords

TFPI - heparanase - coagulation - endothelial cells - tumor
 

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