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Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-β-disrupted diffuse-type gastric carcinoma.

Journal article
Authors Erik Johansson
Akiyoshi Komuro
Caname Iwata
Akifumi Hagiwara
Yuma Fuse
Akira Watanabe
Yasuyuki Morishita
Hiroyuki Aburatani
Keiko Funa
Mitsunobu R Kano
Kohei Miyazono
Published in Cancer science
Volume 101
Issue 11
Pages 2398-403
ISSN 1349-7006
Publication year 2010
Published at Institute of Biomedicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 2398-403
Language en
Keywords Animals, Anoxia, Cell Line, Tumor, Cell Proliferation, drug effects, Gene Expression Regulation, Neoplastic, drug effects, Humans, Immunoblotting, Immunohistochemistry, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Experimental, genetics, metabolism, pathology, Neovascularization, Pathologic, genetics, metabolism, pathology, Protein-Serine-Threonine Kinases, genetics, metabolism, Receptors, Transforming Growth Factor beta, genetics, metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, drug effects, Stomach Neoplasms, genetics, metabolism, pathology, Tissue Inhibitor of Metalloproteinase-2, genetics, metabolism, Transforming Growth Factor beta, metabolism, pharmacology, Transplantation, Heterologous
Subject categories Cell and Molecular Biology


Diffuse-type gastric carcinoma is characterized by rapid progression and poor prognosis. High expression of transforming growth factor (TGF)-β and thick stromal fibrosis are observed in this type of gastric carcinoma. We have previously shown that disruption of TGF-β signaling via introduction of a dominant negative form of the TGF-β type II receptor (dnTβRII) into diffuse-type gastric cancer cell lines, including OCUM-2MLN, caused accelerated tumor growth through induction of tumor angiogenesis in vivo. In the present study, we show that TGF-β induces upregulation of expression of tissue inhibitor of metalloproteinase 2 (TIMP2) in the OCUM-2MLN cell line in vitro, and that expression of TIMP2 is repressed by dnTβRII expression in vivo. Transplantation of the OCUM-2MLN cells to nude mice exhibited accelerated tumor growth in response to dnTβRII expression, which was completely abolished when TIMP2 was coexpressed with dnTβRII. Although the blood vessel density of TIMP2-expressing tumors was only slightly decreased, the degree of hypoxia in tumor tissues was significantly increased and pericytes covering tumor vasculature were decreased by TIMP2 expression in OCUM-2MLN cells, suggesting that the function of tumor vasculatures was repressed by TIMP2 and consequently tumor growth was reduced. These findings provide evidence that one of the mechanisms of the increase in angiogenesis in diffuse-type gastric carcinoma is the downregulation of the anti-angiogenic protein TIMP2.

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