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Transformation of Epithelial Madin-Darby Canine Kidney Cells with p60^v-src Induces Expression of Membrane-Type 1 Matrix Metalloproteinase and Invasiveness¹

Department of Molecular Virology and Oncology, Cancer Research Institute [Y. K., H. S.], and Department of Urology, School of Medicine [Y. K., M. N.], Kanazawa University, Kanazawa, Ishikawa 920; Department of Pathology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 106 [Y. O.]; and Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108 [M. S.], Japan

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is expressed both in carcinoma cells and in surrounding stromal fibroblasts. MT1-MMP localizes to the surface of tumor cells and is thought to play an important role in tumor invasion. To analyze the mechanism of MT1-MMP gene expression in epithelial tumor cells, the dog kidney epithelial cell line Madin-Darby canine kidney (MDCK) was transformed by oncogenes, including v-src, and expression of MT1-MMP was examined. Transformation of MDCK cells with v-src resulted in loss of cell-to-cell contacts and morphological change. Expression of MT1-MMP in v-src-transformed cells was identified by Northern and Western blotting. Gelatin zymography analysis showed that progelatinase A in the culture medium was processed from latent to activated form by MDCK cells transformed with v-src. The MDCK cells transformed by v-src were tumorigenic in the subcutis (ectopic) and kidney (orthotopic) of nude mice and spontaneously metastasized to the lung after orthotopic implantation. These results suggest that MT1-MMP induced by v-src transformation may promote invasiveness of transformed cells.

¹ This work was supported by a grant-in-aid for cancer research from the Ministry of Education, Science, Sports and Culture of Japan.

² To whom requests for reprints should be addressed, at Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920, Japan. Phone: 81-76-265-2750; Fax: 81-76-234-4505; E-mail: vhsato@kenroku.ipc.kanazawa-u.ac.jp.

Received 11/13/97. Accepted 3/18/98.

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