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Inhibition of Tumor Invasion of Smooth Muscle Cell Layers by Recombinant Human Metalloproteinase Inhibitor¹

Department of Pediatrics, Division of Hematology/Oncology [Y. A. D., T. D. Y.] and The Department of Pathology [D. C., H. S.], Children's Hospital of Los Angeles, University of Southern California, Los Angeles, California 90027; and Amgen, Inc. [K. E. L.], Thousand Oaks, California 91320

Matrix metalloproteinases secreted by tumor cells play an important role in the proteolytic degradation of the extracellular matrix during invasion. In a previous study, we showed that the degradation of extracellular matrices by human HT 1080 fibrosarcoma cells is suppressed by endothelial cells. The identification of inhibitors of metalloproteinases secreted by endothelial cells led us to postulate that these inhibitors were responsible for the suppressive effect (Cancer Res., 46: 3580–3586, 1986).

In the present study, we have investigated the inhibitory activity of one of these inhibitors designated metalloproteinase inhibitor (MI)/tissue inhibitor of metalloproteinases (TIMP)-2 on the degradation and invasion of rat smooth muscle cell matrices by two invasive tumor cell lines, the c-Ha-ras-1 transfected rat embryo cell line 4R and the HT 1080 human fibrosarcoma cell line. The inhibitor was obtained in recombinant form from the culture medium of Chinese hamster ovary cells transfected with a human MI complementary DNA.

Recombinant MI/TIMP-2 inhibited several matrix metalloproteinases identified in the culture medium of the tumor cell lines including interstitial collagenase, M_r 72,000 gelatinase (type IV collagenase), and M_r 92,000 gelatinase. Approximately 70% inhibition of the degradation of smooth muscle cell matrices was observed when the recombinant inhibitor was present along with cultured cells at a concentration of 10 µg/ml. Similarly, inhibition of the penetration of a multilayer of growing smooth muscle cells and their surrounding matrix was demonstrated. The inhibitor had no effect on cell growth or attachment.

Thus, recombinant MI/TIMP-2, like TIMP, is a potent inhibitor of tumor invasion. Since both inhibitors are secreted by endothelial cells (J. Biol. Chem., 264: 17445–17453, 1989), they may play an important role in protecting large blood vessels from invasion.

¹ This work was supported by Grant CA 42919 from the NIH, Department of Health and Human Services, to Y. A. D., and by a research agreement between Childrens Hospital of Los Angeles and Amgen, Inc.

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

Received 9/ 6/90. Accepted 1/31/91.

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