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Inhibition of Invasion and Metastasis in Cells Transfected with an Inhibitor of Metalloproteinases¹

Division of Hematology/Oncology, Department of Pediatrics [Y. A. D., N. P.], the Department of Pathology [H. S.], and the Department of Microbiology [S. M. T.], University of Southern California, Los Angeles, California 90033, and AMGEN, Inc. [T. C. B., K. E. L.], Thousand Oaks, California 91320

The balance between levels of metalloproteinases and their corresponding inhibitors is a critical factor in tumor invasion and metastasis. Down-regulation of the activity of these proteases was achieved by transfection of invasive and metastatic rat cells with the complementary DNA for metalloproteinase inhibitor/tissue inhibitor of metalloproteinase 2 (MI/TIMP-2), a novel inhibitor of metalloproteinases recently described. (Y. A. DeClerk et al., J. Biol. Chem., 264: 17445–17453, 1989; W. G. Stetler-Stevenson et al., J. Biol. Chem., 264: 17374–17378, 1989). Secretion of functional MI/TIMP-2 protein in stably transfected cells resulted in a marked decrease in metalloproteinase activity. Partial suppression of the formation of lung colonies after i.v. injection in nude mice was observed in a transfected clone expressing high levels of MI/TIMP-2. Production of MI/TIMP-2 in four clones markedly reduced tumor growth rate in vivo after s.c. injection and completely suppressed local tissue invasion. Thus, down-regulation of metalloproteinase activity has a striking effect on local invasion and partially suppresses hematogenous metastasis.

¹ This work was supported by Grant CA 42919 from the NIH, Department of Health and Human Services, and Grant BE-84 from the American Cancer Society to Y. A. D. and in part by the Neil Bogart Memorial Laboratories of the T. J. Martell Foundation for Leukemia, Cancer and AIDS Research.

² To whom requests for reprints should be addressed, at Children's Hospital of Los Angeles, Division of Hematology/Oncology, 4650 Sunset Boulevard, Los Angeles, CA 90027.

Received 3/26/91. Accepted 11/11/91.

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