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Remodeling of Collagen Matrix by Human Tumor Cells Requires Activation and Cell Surface Association of Matrix Metalloproteinase-2¹

La Jolla Institute for Experimental Medicine [E. I. D., M. A. B., A. S.], and The Scripps Research Institute [R. A. R.], La Jolla, California 92037

We assessed the functional significance of tumor cell-associated matrix metalloproteinase (MMP)-2 in extracellular matrix remodeling compared with that of the soluble enzyme by evaluating the contraction of three-dimensional collagen lattices by human glioma U251.3 and fibrosarcoma HT-1080 cell lines. In this model, the constitutive synthesis and activation of the MMP-2 proenzyme were modulated by stable transfections of tumor cells with cDNA encoding membrane type 1-MMP (MT1-MMP). The efficiency of transfected cells in contracting collagen lattices was shown to be dependent on the MT1-MMP-mediated activation of MMP-2 accompanied by cell surface association of activated MMP-2, on the cell-matrix interactions controlled by collagen-specific integrins, and on the integrity of actin and microtubule cytoskeletons. Each one of these mechanisms was essential but was not sufficient by itself in accomplishing gel contraction by MT1-MMP-transfected cells. Both MMP-2 activation and gel contraction by transfected glioma cells were inhibited by tissue inhibitor of metalloproteinase (TIMP)-2 and the recombinant COOH-terminal domain of MMP-2. However, the kinetics and mechanisms of their inhibitory effects were different, because TIMP-2 and the COOH-terminal domain of MMP-2 preferentially inhibited the MT1-MMP-dependent and autocatalytic steps of MMP-2 activation, respectively. By contrast, TIMP-1, an efficient inhibitor of soluble MMP-2 activity, failed to affect gel contraction. In addition, soluble MMP-2 activited by either organomercurials or cells was not able to induce the contraction of collagen lattices when added to transfected cells. Therefore, soluble activated MMP-2, sensitive to TIMP-1 inhibition, does not mediate collagen gel contraction by tumor cells, whereas the activity of cell surface-associated MMP-2 plays a critical role in remodeling of the extracellular matrix in vitro. These mechanisms of functional and spatial regulation of MMP-2 may also be applicable to different aspects of tissue reorganization in vivo, including cell migration and invasion, angiogenesis, and wound healing.

¹ Supported by California Breast Cancer Research Program Grant 2RB-0028 (to A. S.) and National Cancer Institute Grants CA-52879 (to M. A. B.) and CA-42508 (to R. A. R.).

² To whom requests for reprints should be addressed, at La Jolla Institute for Experimental Medicine, 505 Coast Boulevard South, Suite 404, La Jolla, CA 92037. Phone: (619) 587-8788, ext. 104; Fax: (619) 458-9072; E-mail: strongin@ljiem.org.

Received 1/28/98. Accepted 6/17/98.

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