© 2004 by Oxford University Press
© 2004 Oxford University Press
ARTICLE |
Bone Sialoprotein, Matrix Metalloproteinase 2, and 
v
3 Integrin in Osteotropic Cancer Cell Invasion
Affiliations of authors: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (AK, KUEO, NSF, LWF); Division of Geriatrics, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (NSF)
Correspondence to: Abdullah Karadag, MD, PhD, MSc, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, 9000 Rockville Pike, Bldg. 30, Rm. 228, Bethesda, MD 20892-4320 (e-mail: akaradag{at}dir.nidcr.nih.gov)
Background: Bone sialoprotein (BSP) interacts separately with both matrix metalloproteinase 2 (MMP-2) and integrin 
v
3 and is overexpressed in many metastatic tumors. Its role in tumor biology, however, remains unclear. We investigated whether BSP enhances cancer cell invasiveness by forming a trimolecular complex with MMP-2 and cell-surface integrin v3. Methods: Invasiveness of breast, prostate, lung, and thyroid tumor cell lines was measured with a modified Boyden chamber assay. Binding and co-localization of BSP, MMP-2, and integrin v3 were investigated with immunoprecipitation and in situ hybridization. All statistical tests were two-sided. Results: Treatment with BSP increased invasiveness of many breast, prostate, lung, and thyroid cancer cells through Matrigel in a dose-dependent manner. BSP at 50 nM increased the invasiveness of SW-579 thyroid cancer cells (95.2 units, 95% confidence interval [CI] = 90.4 to 100 units) by approximately 10-fold compared with that of untreated control SW-579 cells (9.1 units, 95% CI = 5.7 to 12.5 units) (P<.001). Addition of an inactive mutated BSP, in which BSP's integrin-binding RGD tripeptide was altered, or addition of integrin v3-blocking antibodies resulted in invasiveness equivalent to that of untreated cells. Inhibiting cellular MMP-2 activity with chemical inhibitors or a specific antibody also blocked BSP-enhanced invasiveness. Osteopontin and dentin matrix protein 1, proteins related to BSP that also bind integrin v3 and form complexes with other MMPs (but not MMP-2), did not enhance invasiveness. Immunoprecipitation showed that a complex containing BSP, integrin v3, and MMP-2 formed in vitro. Addition of BSP increased the amount of MMP-2 bound by cells in an integrin-dependent fashion. Co-expression of BSP, integrin v3, and MMP-2 in papillary thyroid carcinoma cells was shown by in situ hybridization. Conclusion: Cancer cells appear to become more invasive when BSP forms a cell-surface trimolecular complex by linking MMP-2 to integrin v3.
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