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Tissue inhibitor of metalloproteinases‐1 (TIMP‐1) inhibits tumor growth and angiogenesis in the TIMP‐1 transgenic mouse model
Author(s) -
Ikenaka Yasuhide,
Yoshiji Hitoshi,
Kuriyama Shigeki,
Yoshii Junichi,
Noguchi Ryuichi,
Tsujinoue Hirohisa,
Yanase Koji,
Namisaki Tadashi,
Imazu Hiroo,
Masaki Tsutomu,
Fukui Hiroshi
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11094
Subject(s) - matrix metalloproteinase , angiogenesis , neovascularization , genetically modified mouse , cancer research , biology , in vitro , in vivo , tissue inhibitor of metalloproteinase , transgene , endocrinology , chemistry , microbiology and biotechnology , biochemistry , gene
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.