Expression of collagenase-1 (MMP-1) promotes melanoma growth through the generation of active transforming growth factor-beta.
Tumor cell invasion through basement membranes and into stromal tissue are key steps for promoting growth and metastasis. Tumor cells express various extracellular-matrix-degrading enzymes such as matrix metalloproteinases (MMPs) to degrade extracellular matrix components to facilitate tumor migration and invasion. Histological and clinical studies suggest a role for MMP-1 (collagenase-1) in malignant melanoma invasion. In this study, we evaluated MMP-1 in regulating malignant phenotypes of human melanoma cells by generating human melanoma cells stably transfected with pro-MMP-1 cDNA. The transfectants expressed the active form of MMP-1 associated with cells and showed enhanced invasive and growth abilities in type I collagen gel. Furthermore, MMP-1 expression promoted anchorage-independent growth, which was inhibited in the presence of type II transforming growth factor (TGF)-beta receptor:Fc fusion protein that scavenges TGF-beta receptors. Finally, we demonstrated that MMP-1 directly generated active TGF-beta from its latent form. Thus, these results suggest that MMP-1 produced from melanoma cells would play a role in tumor progression by both degrading matrix proteins and generating active growth factors such as TGF-beta in vivo.
Iida
Joji
J
Department of Laboratory Medicine and Pathology, University of Minnesota, Comprehensive Cancer Center, Minneapolis 55455, USA. iidax002@tc.unm.edu
McCarthy
James B
JB
D000818:Animals; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000737:chemistry; D004847:Epithelial Cells / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000166:cytology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000737:chemistry*; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism; D008907:Mink; D008954:Models, Biological; D009362:Neoplasm Metastasis; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D024042:Collagen Type I; D016212:Transforming Growth Factor beta; D020781:Matrix Metalloproteinase 1