title: Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibits tumor growth and angiogenesis in the TIMP-1 transgenic mouse model.
abstract: The tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) has been recognized as a multifunctional protein. The role of TIMPs in cancer remains the subject of conflicting reports with an antitumor activity or a tumor growth stimulation activity by several mechanisms. The aim of our study is to investigate the effect of ectopic TIMP-1 overexpression on the primary transplanted tumor growth. We employed transgenic mice overexpressing the human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/enhancer (TIMP-Tg-mice) and producing high serum levels of TIMP-1. We used the transplantable Ehrlich tumor cells in the current study. The allograft study revealed that the tumor growth in the TIMP-Tg-mice was more significantly inhibited than control (Cont) mice by associated suppression of neovascularization in the tumor. The in vitro studies showed that the recombinant TIMP-1 (rTIMP-1) did not affect the proliferation of the endothelial cells (ECs) and tumor cells, suggesting that the tumor suppressive effect of TIMP-1 was not due to cytotoxicity. TIMP-1 significantly inhibited EC tubular formation in vitro. Furthermore, TIMP-1 treatment did not affect the levels of matrix metalloproteinase (MMP)-2 and MMP-9 mRNA in the Ehrlich tumor cells in vitro, although these expressions in the tumor were markedly suppressed in the TIMP-Tg-mice, compared to the Cont-mice at the end of the experiment. These results suggested that the ectopically overexpressed TIMP-1 inhibited the tumor growth by angiogenesis suppression.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Nara, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshii
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Tsujinoue
authors.forename: Koji
authors.initials: K
authors.lastname: Yanase
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Hiroo
authors.initials: H
authors.lastname: Imazu
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism; D002455:Cell Division; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism* / Q000502:physiology*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9