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Matrilysin (MMP-7) induces homotypic adhesion of human colon cancer cells and enhances their metastatic potential in nude mouse model

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Abstract

Matrilysin (MMP-7) is thought to contribute to invasive growth and metastasis of colon carcinoma and many other human cancers. The present study demonstrates that treatment of human colon carcinoma cells with active matrilysin induces cell aggregation in vitro and promotes liver metastasis in nude mice. When two kinds of colon carcinoma cell lines were incubated with active matrilysin, this enzyme efficiently bound to the cell surface and induced loose cell aggregation, which led to E-cadherin-mediated tight cell aggregation. Synthetic MMP inhibitors inhibited both the membrane binding of matrilysin and matrilysin-induced cell aggregation, while TIMP-2 inhibited only the cell aggregation. Two other active MMPs, stromelysin and gelatinase A, neither bound to cell membrane nor induced cell aggregation. Tumor cells in loose cell aggregates could reaggregate even after they were freed from matrilysin and dispersed. When injected into the spleen of nude mice, the tumor cells in the stable aggregates produced much larger metastatic nodules in the livers than control cells and those in the loose aggregates. These results suggest that matrilysin may enhance metastatic potential of tumor cells by processing a cell surface protein(s) and thereby inducing loose and then tight aggregation of tumor cells.

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Acknowledgements

We are grateful to Mr J Tsunezumi, Miss K Moriyama, and Dr S Hasegawa for technical support and Drs H Yasumitsu and Y Tsubota for helpful suggestions and discussions. This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology and from the Ministry of Welfare and Labor of Japan.

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Authors and Affiliations

  1. Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, 641-12, Maioka-cho, Totsuka-ku, Yokohama, 244-0813, Japan

    Mitomu Kioi, Kazuhiro Yamamoto, Shouichi Higashi, Naohiko Koshikawa & Kaoru Miyazaki

  2. Department of Oral Maxillofacial Surgery, Yokohama City University School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0008, Japan

    Mitomu Kioi & Kiyohide Fujita

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  1. Mitomu Kioi
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  2. Kazuhiro Yamamoto
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  3. Shouichi Higashi
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  4. Naohiko Koshikawa
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  5. Kiyohide Fujita
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  6. Kaoru Miyazaki
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Correspondence to Kaoru Miyazaki.

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Kioi, M., Yamamoto, K., Higashi, S. et al. Matrilysin (MMP-7) induces homotypic adhesion of human colon cancer cells and enhances their metastatic potential in nude mouse model. Oncogene 22, 8662–8670 (2003). https://doi.org/10.1038/sj.onc.1207181

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