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Expression of Metalloproteinases and Metalloproteinase Inhibitors by Fetal Astrocytes and Glioma Cells¹

Department of Pathology [G. A., J. T. R., J. H. M.], Brain Tumor Research Center of the Department of Neurological Surgery [J. T. R., M. E. B., J. R. G., M. L. R.], and Laboratory of Radiology and Environmental Health [K. B., M. J. B., J. H. M.], University of California, San Francisco, California 94143

Metalloproteinases have been implicated as important factors mediating the tissue migration of a variety of normal and transformed cells. The conditioned medium (CM) of fetal human astrocytes and five glioma cell lines did not degrade azocoll in suspension, but several proteolytic activities, inhibitable by 1,10-phenanthroline, were detected on sodium dodecyl sulfate-polyacrylamide gels containing gelatin. Both cell types secreted three major proteolytic species (M_r 65,000, 57,000, and 52,000). Two of the glioma lines secreted an additional proteinase (M_r 92,000). After treatment with 12-O-tetradecanoylphorbol-13-acetate, the secretion of the M_r 92,000, 57,000, and 52,000 proteinases was induced or enhanced in all of the cells. The M_r 92,000 and 65,000 proteinases bound specifically to a gelatin affinity column. When purified by preparative gel electrophoresis, the M_r 65,000 proteinase was found to degrade type IV procollagen. The M_r 57,000 and 52,000 species were precipitated by anti-collagenase IgG. Tissue inhibitor of metalloproteinases was detected in the CM of all of the cells by substrate gel analysis and immunoprecipitation of [³⁵S]methionine-labeled proteins with anti-tissue inhibitor of metalloproteinases IgG. The glioma lines also secreted various amounts of two smaller inhibitors of metalloproteinases (IMPs), also seen in rabbit brain capillary endothelial cell CM (IMP-1 at M_r 22,000 and IMP-2 at M_r 19,000), and an inhibitor not previously identified (IMP-3 at M_r 16,500). 12-O-Tetradecanoylphorbol-13-acetate stimulated the secretion of tissue inhibitor of metalloproteinases in all of the cells and induced IMPs in some of the glioma lines. When gel filtration chromatography of concentrated CM was used to resolve inhibitors from proteinases, the isolated proteinases had activity against azocoll and the glycoprotein and collagen components of an in vitro model of the extracellular matrix. The secretion of a battery of metalloproteinases by astrocytes may be important in facilitating astrocytic migration during development and in pathological conditions such as inflammation or local invasion of astrocytic neoplasms.

¹ This work was supported by a National Science Foundation Minority Fellowship and a Ford Foundation Dissertation Year Fellowship (G. A.), by the Medical Research Council of Canada (J. T. R.), by Grants CA-31882 and CA-13525 from the National Cancer Institute and a grant from the Preuss Foundation (M. L. R.), by Office of Health and Environmental Research of the United States Department of Energy Contract DE-AC03-76-SF01012 (K. B., M. J. B., J. H. M.), by Grant AM32746 from the NIH (M. J. B.), and by Grant AI 20452 from the National Institute of Allergy and Infectious Disease (J. H. M.).

² Present address: Department of Anatomy S-1334, University of California, San Francisco, CA 94143.

³ To whom requests for reprints should be addressed.

Received 7/20/89. Revised 12/15/89.

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