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Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibits tumor growth and angiogenesis in the TIMP-1 transgenic mouse model

✍ Scribed by Yasuhide Ikenaka; Hitoshi Yoshiji; Shigeki Kuriyama; Junichi Yoshii; Ryuichi Noguchi; Hirohisa Tsujinoue; Koji Yanase; Tadashi Namisaki; Hiroo Imazu; Tsutomu Masaki; Hiroshi Fukui


Publisher
John Wiley and Sons
Year
2003
Tongue
French
Weight
224 KB
Volume
105
Category
Article
ISSN
0020-7136

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✦ Synopsis


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. © 2003 Wiley‐Liss, Inc.


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