Bone morphogenetic proteins induce expression of metalloproteinases in melanoma cells and fibroblasts.

Bone morphogenetic proteins are secreted growth factors which belong to the TGFbeta super family. In recent studies, we showed that the expression of BMP-4 and -7 is induced in melanoma cells in comparison to normal melanocytes. Functional analyses revealed that BMPs are inevitable factors for migration and invasion processes of melanoma cells; however, the role of BMPs in degradation and remodelling of the extracellular matrix remained unknown. We discovered that melanoma cell clones with reduced BMP activity, generated by stable transfection with an antisense BMP-4 construct or with the BMP inhibitor chordin, showed reduced expression of MMP-1, -2, -3 and -9. Moreover, BMPs displayed paracrine effects on stromal fibroblasts. Treatment of fibroblasts with BMP-2 or -4 led to increased MMP-1, -2, -3 and -13 expression. These data show that BMPs play an important role in dissemination of tumour cells from the primary tumour, either by enhancing the matrix degrading capacity of melanoma cells themselves or by stimulating tumour surrounding fibroblasts to induce expression of matrix metalloproteinases.