title: Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: effect on in vivo mammary tumor growth and angiogenesis.
abstract: 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.
authors: Laboratories of Tumor and Development Biology, University of Liège, Sart-Tilman, 4000 Liege, Belgium.
authors: A
authors: A
authors: Hajitou
authors: N E
authors: NE
authors: Sounni
authors: L
authors: L
authors: Devy
authors: C
authors: C
authors: Grignet-Debrus
authors: J M
authors: JM
authors: Lewalle
authors: H
authors: H
authors: Li
authors: C F
authors: CF
authors: Deroanne
authors: H
authors: H
authors: Lu
authors: A
authors: A
authors: Colige
authors: B V
authors: BV
authors: Nusgens
authors: F
authors: F
authors: Frankenne
authors: A
authors: A
authors: Maron
authors: P
authors: P
authors: Yeh
authors: M
authors: M
authors: Perricaudet
authors: Y
authors: Y
authors: Chang
authors: C
authors: C
authors: Soria
authors: C M
authors: CM
authors: Calberg-Bacq
authors: J M
authors: JM
authors: Foidart
authors: A
authors: A
authors: Noël
mesh_terms: 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
chemical_list: 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