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Lombardi Cancer Center and Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007 [C. G., H. P., E. W. T.]; Laboratoire de Biologie des Tumeurs et du Développement, Tour de Pathologie, C.H.U. Sart-Tilman, Université de Liège, Liège, Belgium [C. G., J-M. F.]; Department of Biological Structure, University of Washington, Seattle, Washington 98195-7420 [J. A. B., E. H. S.]; and VBCRC Invasion and Metastasis Unit, St. Vincent's Institute of Medical Research and Department of Surgery, University of Melbourne, Melbourne, 3065 Australia [E. W. T.]
Activation of the matrix metalloproteinase 2 (MMP-2) has been shown to play a major role in the proteolysis of extracellular matrix (ECM) associated with tumor invasion. Although the precise mechanism of this activation remains elusive, levels of the membrane type 1-MMP (MT1-MMP) at the cell surface and of the tissue inhibitor of MMP-2 (TIMP-2) appear to be two important determinants. Induction of MMP-2 activation in cells cultivated on collagen type I gels indicated that the ECM is important in the regulation of this process. In this study, we show that SPARC/osteonectin, a small ECM-associated matricellular glycoprotein, can induce MMP-2 activation in two invasive breast cancer cell lines (MDA-MB-231 and BT549) but not in a noninvasive counterpart (MCF-7), which lacks MT1-MMP. Using a set of peptides from different regions of SPARC, we found that peptide 1.1 (corresponding to the NH2-terminal region of the protein) contained the activity that induced MMP-2 activation. Despite the requirement for MT1-MMP, seen in MCF-7 cells transfected with MT1-MMP, the activation of MMP-2 by SPARC peptide 1.1 was not associated with increased steady-state levels of MT1-MMP mRNA or protein in either MT1-MMP-transfected MCF-7 cells or constitutively expressing MDA-MB-231 and BT549 cells. We did, however, detect decreased levels of TIMP-2 protein in the media of cells incubated with peptide 1.1 or recombinant SPARC; thus, the induction of MMP-2 activation by SPARC might be due in part to a diminution of TIMP-2 protein. We conclude that SPARC, and specifically its NH2-terminal domain, regulates the activation of MMP-2 at the cell surface and is therefore likely to contribute to the proteolytic pathways associated with tumor invasion.
1 This work was supported by NIH Grants CA61344, GM40711, HL18645, and DK47659. C. G. was supported in part by the NATO Foundation, La Foundation Rose et Jean Hoguet, La Fondation Léon-Frédéricq, La Fondation Cancérologique St-Michel, and Le Prix Van Beirs. This work was also supported in part by the Lombardi Cancer Center cores for Macromolecules Synthesis & Sequencing and Tissue Culture USPHS Grant 2P30-CA-51008.
2 To whom requests for reprints should be addressed, at VBCRC Invasion and Metastasis Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia. Phone: 61-3-9288-2480; Fax: 61-3-9416-2676; E-mail: rik@ariel.its.unimelb.edu.au.
Received 5/21/98. Accepted 10/ 5/98.
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