Aminopeptidase inhibitor bestatin stimulates microvascular endothelial cell invasion in a fibrin matrix

Yvette van Hensbergen; Henk J. Broxterman; Erna Peters; Sareena Rana; Yvonne W. Elderkamp; Victor W. M. van Hinsbergh; Pieter Koolwijk

doi:10.1160/TH03-03-0144

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(05): 921-929
DOI: 10.1160/TH03-03-0144

Cellular Proteolysis and Oncology

Schattauer GmbH

Aminopeptidase inhibitor bestatin stimulates microvascular endothelial cell invasion in a fibrin matrix

Authors

Yvette van Hensbergen

¹Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
Henk J. Broxterman

¹Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

³Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
Erna Peters

²Gaubius Laboratory, TNO-PG, The Netherlands
Sareena Rana

¹Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
Yvonne W. Elderkamp

¹Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
Victor W. M. van Hinsbergh

²Gaubius Laboratory, TNO-PG, The Netherlands

³Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
Pieter Koolwijk

²Gaubius Laboratory, TNO-PG, The Netherlands

Abstract

Summary

The aminopeptidase inhibitor bestatin has been shown to have anti-angiogenic effects in a number of model systems. These effects are thought to result from inhibition of CD13 activity. Because tumor angiogenesis can evolve in a fibrin-rich stroma matrix we have studied for the first time the effects of bestatin on microvascular endothelial capillary-like tube formation in a fibrin matrix. Bestatin enhanced the formation of capillary-like tubes dose-dependently. Its effects were apparent at 8 µM; the increase was 3.7-fold at 125 µM; while high concentrations (>250 µM), that were shown to have anti-angiogenic effects in other systems, caused extensive matrix degradation. Specific CD13-blocking antibodies WM15 and MY-7, and the aminopeptidase inhibitors amastatin and actinonin also enhanced capillary-like tube formation (maximally 1.5-fold), but these effects did not reach statistical significance. The effect of bestatin was not due to a change in uPAR availability because the relative involvement of the u-PA/u-PAR activity was not altered by bestatin. In view of the present findings we hypothesize that aminopeptidases other than CD13 predominantly contribute to the observed pro-angiogenic effect of bestatin in a fibrin matrix. The identification of this novel effect of bestatin is important in the light of the proposed use of bestatin as anti-angiogenic and/or anti-tumor agent.

Keywords

Bestatin - CD13 - angiogenesis - fibrin - u-PAR

Full Text

References

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