This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nonaka, T. Articles by Seiki, M. Search for Related Content PubMed PubMed Citation Articles by Nonaka, T. Articles by Seiki, M.

Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato, Tokyo, Japan

Requests for reprints: Motoharu Seiki, Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato, Tokyo 108-8639, Japan. Phone: 81-3-5449-5255; Fax: 81-3-5449-5414. E-mail: mseiki{at}ims.u-tokyo.ac.jp

Membrane type 1 matrix metalloproteinase (MT1-MMP) is a potent modulator of the pericellular environment and promotes tumor cell invasion and proliferation in many types of tumor. The activation of proMMP-2 and processing of collagen I by MT1-MMP have been thought to be important for its tumor-promoting function. These activities can be inhibited by mutant forms of MT1-MMP lacking the catalytic domain. However, the effect of such dominant-negative mutants has never been evaluated in vivo. Various mutants lacking the catalytic domain (dCAT) were prepared and confirmed to inhibit MT1-MMP activity in human fibrosarcoma HT1080 cells, and tumor cells expressing these mutants were implanted s.c. into nude mice to monitor tumor formation. Only the membrane-anchored form of a dCAT construct through the transmembrane domain [dCAT(1)] showed potent antitumor activity not only in HT1080 cells but also in gastric carcinoma MKN28 and MKN45 cells expressing MT1-MMP. A soluble form of dCAT lacking the transmembrane domain did not show such activity. The expression of dCAT(1) in MKN28 or MKN45 further prevented the metastatic spread of tumor cells into the peritoneal cavity; however, dCAT(1) showed no effect against TMK-1, another gastric carcinoma cell line expressing no MT1-MMP. It is of note that the tumorigenicity of TMK-1 cells enhanced by MT1-MMP overexpression was, in turn, canceled by the additional expression of dCAT(1). Thus, MT1-MMP expressed in tumor cells seems to play a pivotal role in tumor growth in mice. The results also suggest new possibilities to abrogate the tumor-promoting function of MT1-MMP other than the conventional protease inhibitor–based approach.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Y. Itoh is currently at the Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, United Kingdom.

Received 4/26/05; revised 6/ 4/05; accepted 6/14/05.