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Dentin Matrix Protein 1 Enhances Invasion Potential of Colon Cancer Cells by Bridging Matrix Metalloproteinase-9 to Integrins and CD44

¹ Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Department of Health and Human Services, Bethesda, Maryland and ² Division of Geriatrics, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Larry W. Fisher, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Department of Health and Human Services, Room 228, Building 30, 9000 Rockville Pike, Bethesda, MD 20892-4320. Phone: 301-496-5769; Fax: 301-402-0824; E-mail: lfisher{at}dir.nidcr.nih.gov.

The up-regulation of various matrix metalloproteinases (MMP), certain cell receptors such as integrins and CD44, and the SIBLING family of integrin-binding glycophosphoproteins have been reported separately and in various combinations for many types of tumors. The mechanisms by which these different proteins may be interacting and enhancing the ability of a cancer cell to survive and metastasize have become an interesting issue in cancer biology. Dentin matrix protein 1 (DMP1) has been known for a number of years to bind to CD44 and ArgGlyAsp sequence–dependent integrins. This SIBLING was recently shown to be able to specifically bind and activate proMMP-9 and to make MMP-9 much less sensitive to inhibition by tissue inhibitors of metalloproteinases and synthetic inhibitors. In this study, we used a modified Boyden chamber assay to show that DMP1 enhanced the invasiveness of the MMP-9 expressing colon cancer cell line, SW480, through Matrigel in a dose-dependant manner. DMP1 (100 nmol/L) increased invasion 4-fold over controls (86.1 ± 13.9 versus 22.3 ± 9.8, P < 0.001). The enhanced invasive potential required the presence of MMP-9 and at least one of the cell surface receptors, CD44, _vß₃, or _vß₅ integrin. The bridging of MMP-9 to the cell surface receptors was shown by both pull-down and fluorescence activated cell sorting experiments. Because all of these proteins were also shown by immunohistochemistry to be expressed in serial sections of a colon adenocarcinoma, we have hypothesized that the MMP-9/DMP1/cell surface complexes observed to enhance cell invasion in vitro may be aiding metastatic events in vivo. (Cancer Res 2005; 65(24): 11545-52)

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