Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: effect on in vivo mammary tumor growth and angiogenesis.
The tissue inhibitor of metalloproteinases-2 (TIMP-2) has at least two independent functions, i.e., regulation of matrix metalloproteinases and growth promoting activity. We investigated the effects of TIMP-2 overexpression, induced 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 with a retroviral expression vector for the fgf-4 oncogene, are highly tumorigenic and overproduce vascular endothelial growth factor (VEGF). Despite a promotion of the in vitro growth rate of EF43.fgf-4 cells overexpressing timp-2, the in vivo tumor growth was delayed. At day 17 post-cell injection, the volume of tumor derived from TIMP-2-overexpressing cells was reduced by 80% as compared with that obtained with control cells. Overexpression of TIMP-2 was associated with a down-regulation of VEGF expression in vitro and in vivo, 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 growth and angiogenesis of mammary carcinoma in vivo and that down-regulation of VEGF expression may play an important role in this TIMP-2-mediated antitumoral and antiangiogenic effects. Finally the in vivo delivery of TIMP-2, as assessed by i.v. injection of recombinant adenoviruses vectors, significantly reduced the growth of the EF43.fgf-4-induced tumors. This effect of TIMP-2 was shown to be equally comparable with that of angiostatin, a known potent inhibitor of angiogenesis.
Hajitou
A
A
Laboratories of Tumor and Development Biology, University of Liège, Sart-Tilman, 4000 Liege, Belgium.
Sounni
N E
NE
Devy
L
L
Grignet-Debrus
C
C
Lewalle
J M
JM
Li
H
H
Deroanne
C F
CF
Lu
H
H
Colige
A
A
Nusgens
B V
BV
Frankenne
F
F
Maron
A
A
Yeh
P
P
Perricaudet
M
M
Chang
Y
Y
Soria
C
C
Calberg-Bacq
C M
CM
Foidart
J M
JM
Noël
A
A
D000256:Adenoviridae / Q000235:genetics; D043168:Angiostatins; D000818:Animals; D002455:Cell Division; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics; D018014:Gene Transfer Techniques; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010958:Plasminogen / Q000235:genetics / Q000502:physiology; D051381:Rats; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C112971:fibroblast growth factor 14; D019716:Tissue Inhibitor of Metalloproteinase-2; D005346:Fibroblast Growth Factors; D043168:Angiostatins; D010958:Plasminogen