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Extracellular and intracellular mechanisms that mediate the metastatic activity of exogenous osteopontin
Article first published online: 17 FEB 2009
Copyright © 2009 American Cancer Society
Volume 115, Issue 8, pages 1753–1764, 15 April 2009
How to Cite
Mandelin, J., Lin, E. C. K., Hu, D. D., Knowles, S. K., Do, K.-A., Wang, X., Sage, E. H., Smith, J. W., Arap, W. and Pasqualini, R. (2009), Extracellular and intracellular mechanisms that mediate the metastatic activity of exogenous osteopontin. Cancer, 115: 1753–1764. doi: 10.1002/cncr.24170
- Issue published online: 6 APR 2009
- Article first published online: 17 FEB 2009
- Manuscript Accepted: 4 SEP 2008
- Manuscript Revised: 12 AUG 2008
- Manuscript Received: 8 MAY 2008
- National Institutes of Health. Grant Numbers: CA69306, CA30199, CA90270
- Department of Defense. Grant Number: DAMD 17-98-1-8041
- California Breast Cancer Research Program
- The Army Breast Cancer Research Program
- Gillson-Longenbaugh Foundation
- Helsingin Sanomat Centennial Foundation
- Emil Aaltonen Foundation
- Research and Science Foundation of Farmos
- Maud Kuistila Memorial Foundation
Osteopontin affects several steps of the metastatic cascade. Despite direct correlation with metastasis in experimental systems and in patient studies, the extracellular and intracellular basis for these observations remains unsolved. In this study, the authors used human melanoma and sarcoma cell lines to evaluate the effects of soluble osteopontin on metastasis.
Exogenous osteopontin or negative controls, including a site-directed mutant osteopontin, were used in functional assays in vitro, ex vivo, and in vivo that were designed to test the extracellular and intracellular mechanisms involved in experimental metastasis.
In the extracellular environment, the results confirmed that soluble osteopontin is required for its prometastatic effects; this phenomenon is specific, arginine-glycine-aspartic acid (RGD)-dependent, and evident in experimental models of metastasis. In the intracellular environment, osteopontin initially induced rapid tyrosine 418 (Tyr-418) dephosphorylation of the cellular homolog of the Rous sarcoma virus (c-Src), with decreases in actin stress fibers and increased binding to the vascular endothelium. This heretofore undescribed Tyr dephosphorylation was followed by a tandem c-Src phosphorylation after tumor cell attachment to the metastatic site.
The results of this study revealed a complex molecular interaction as well as a dual role for osteopontin in metastasis that depends on whether tumor cells are in circulation or attached. Such context-dependent functional insights may contribute to antimetastasis strategies. Cancer 2009. © 2009 American Cancer Society.