Title
Aminopeptidase inhibitor bestatin stimulates microvascular endothelial cell invasion in a fibrin matrix
Author
van Hensbergen, Y.
Broxterman, H.J.
Peters, E.
Rana, S.
Elderkamp, Y.W.
van Hinsbergh, V.W.M.
Koolwijk, P.
Gaubius Instituut TNO
Publication year
2003
Abstract
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.
Subject
Biomedical Research
Angiogenesis
Bestatin
u-PAR
actinonin
amastatin
antibody
antineoplastic agent
basic fibroblast growth factor
enzyme inhibitor
microsomal aminopeptidase
MY 7 antibody
unclassified drug
urokinase
urokinase receptor
vasculotropin
WM15 antibody
angiogenesis
cell invasion
concentration (parameters)
controlled study
dose response
drug effect
endothelium cell
enzyme activity
human cell
hypothesis
priority journal
protein expression
stroma
tumor
vascular endothelium
Aminopeptidases
Antigens, CD13
Cell Movement
Cells, Cultured
Dose-Response Relationship, Drug
Endothelium, Vascular
Fibrin
Humans
Integrins
Leucine
Microcirculation
Neovascularization, Physiologic
Receptors, Cell Surface
Umbilical Veins
Urinary Plasminogen Activator
To reference this document use:
http://resolver.tudelft.nl/uuid:cfe7d76b-cb73-413b-8bad-6939dd911242
TNO identifier
237379
ISSN
0340-6245
Source
Thrombosis and Haemostasis, 90 (5), 921-929
Document type
article