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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

Yvette van Hensbergen
1   Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
,
Henk J. Broxterman
1   Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
3   Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
,
Erna Peters
2   Gaubius Laboratory, TNO-PG, The Netherlands
,
Sareena Rana
1   Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
,
Yvonne W. Elderkamp
1   Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
,
Victor W. M. van Hinsbergh
2   Gaubius Laboratory, TNO-PG, The Netherlands
3   Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
,
Pieter Koolwijk
2   Gaubius Laboratory, TNO-PG, The Netherlands
› Author AffiliationsFinancial support: This study was supported by the Spinoza Award to H.M. Pinedo, Head of the Department of Medical Oncology, VU Medical Center, Amsterdam, The Netherlands, and by the Stichting Vanderes, grant 65.
Further Information

Publication History

Received 11 March 2003

Accepted after resubmission 18 July 2003

Publication Date:
05 December 2017 (online)

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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
 

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