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Interference with the Complement System by Tumor Cell Membrane Type-1 Matrix Metalloproteinase Plays a Significant Role in Promoting Metastasis in Mice

¹ Cell Adhesion and Extracellular Matrix Biology, Burnham Institute for Medical Research, La Jolla, California and ² Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina

Requests for reprints: Alex Y. Strongin, Cell Adhesion and Extracellular Matrix Biology, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: 858-713-6271; Fax: 858-713-9925; E-mail: strongin{at}burnham.org.

Neoplasms have developed strategies to protect themselves against the complement-mediated host immunity. Invasion- and metastasis-promoting membrane type-1 (MT1) matrix metalloproteinase (MMP) is strongly associated with many metastatic cancer types. The relative importance of the individual functions of MT1-MMP in metastasis was, however, unknown. We have now determined that the expression of murine MT1-MMP in murine melanoma B16F1 cells strongly increased the number of metastatic loci in the lungs of syngeneic C57BL/6 mice. In contrast, MT1-MMP did not affect the number of metastatic loci in complement-deficient C57BL/6-C3^–/– mice. Our results indicated, for the first time, that the anticomplement activity of MT1-MMP played a significant role in promoting metastasis in vivo and determined the relative importance of the anticomplement activity in the total metastatic effect of this multifunctional proteolytic enzyme. We believe that our results shed additional light on the functions of MT1-MMP in cancer and clearly make this protease a promising drug target in metastatic malignancies. (Cancer Res 2006; 66(12): 6258-63)

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