Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: Effect on in vivo mammary tumor growth and angiogenesis

Citation
A. Hajitou et al., Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: Effect on in vivo mammary tumor growth and angiogenesis, CANCER RES, 61(8), 2001, pp. 3450-3457
Citations number
42
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
61
Issue
8
Year of publication
2001
Pages
3450 - 3457
Database
ISI
SICI code
0008-5472(20010415)61:8<3450:DOVEGF>2.0.ZU;2-M
Abstract
The tissue inhibitor of metalloproteinases-2 (TIMP-2) has at least two inde pendent functions, ie., regulation of matrix metalloproteinases and growth promoting activity. We investigated the effects of TIMP-2 overexpression, i nduced by retroviral mediated gene transfer, on the in vivo development of mammary tumors in syngeneic mice inoculated with EF43.fgf-4 cells. The EF43 .fgf-4 cells established by stably infecting the normal mouse mammary EF43 cells dth a retroviral expression vector for the fgf-4 oncogene, are highly tumorigenic and overproduce vascular endothelial growth factor (VEGF). Des pite a promotion of the in vitro growth rate of EF43.fgf-4 cells overexpres sing timp-2, the in vivo tumor growth was delayed. At day 17 post-cell inje ction, the volume of tumor derived from TIMP-2-overexpressing cells was red uced by 80% as compared with that obtained with control cells. Overexpressi on of TIMP-2 was associated with a down-regulation of VEGF expression in vi tro and ill vice, a reduction of vessel size, density, and blood supply in the induced tumors. In addition, TIMP-2 completely inhibited the angiogenic activity of EF43.fgf-4 cell-conditioned medium in vitro using a rat aortic ring model. Our findings suggest that overexpression of TIMP-2 delays grow th and angiogenesis of mammary carcinoma in vivo and that down-regulation o f VEGF expression may play an important role in this TIMP-2-mediated antitu moral and antiangiogenic effects. Finally the in vivo delivery of TIMP-2, a s assessed by i.v. injection of recombinant adenoviruses vectors, significa ntly reduced the growth of the EF43.fgf-4-induced tumors. This effect of TI MP-2 mas shown to be equally comparable with that of angiostatin, a known p otent inhibitor of angiogenesis.