Stromal Expression of MMP-13 Is Required for Melanoma Invasion and Metastasis

Tumor invasion and metastasis of malignant melanoma have been shown to require proteolytic degradation of the extracellular environment achieved primarily by enzymes of the matrix metalloproteinases (MMP) family. We have earlier shown that increased enzyme activity is localized at the border of tumor cells and the adjacent peritumoral connective tissue, emphasizing the importance of tumor-stroma interactions in the regulation of MMP activity. To confirm the role of stroma-derived MMP-13 in the invasion process, we investigated the invasiveness of melanoma cells upon intradermal injection in mice with complete inactivation of MMP-13. Tumor growth was significantly impaired in mmp-13−/- mice and most significant at early time points as compared with wild-type littermates. Moreover, metastasis to various organs was reduced to 17.6 vs 30% in lungs, 2.9 vs 30% in the liver. Strikingly, ablation of MMP-13 completely abrogated formation of metastasis in the heart (0 vs 40%). Notably, decreased tumor growth in mmp-13−/- mice was associated with reduced blood vessel density. In addition, decreased blood vessel permeability in the tumors was measured by magnetic resonance imaging of tumor-bearing animals. These data suggest an important role of MMP-13 in tumor growth and an unexpected role in organ-specific metastasis of melanoma cells.