Aminopeptidase inhibitor bestatin stimulates microvascular endothelial cell invasion in a fibrin matrix.
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 micro M; the increase was 3.7-fold at 125 micro M; while high concentrations (>250 micro M), 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.
van Hensbergen
Yvette
Y
Department of Medical Oncology, Amsterdam, VU University Medical Center, The Netherlands.
Broxterman
Henk J
HJ
Peters
Erna
E
Rana
Sareena
S
Elderkamp
Yvonne W
YW
van Hinsbergh
Victor W M
VW
Koolwijk
Pieter
P
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D018826:CD13 Antigens / Q000032:analysis; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000187:drug effects; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008833:Microcirculation / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D014471:Umbilical Veins; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology
D016023:Integrins; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D005337:Fibrin; D000626:Aminopeptidases; D018826:CD13 Antigens; D014568:Urokinase-Type Plasminogen Activator; D007930:Leucine; C012211:ubenimex