title: Membrane-type-3 matrix metalloproteinase (MT3-MMP) functions as a matrix composition-dependent effector of melanoma cell invasion.
abstract: In primary human melanoma, the membrane-type matrix metalloproteinase, MT3-MMP, is overexpressed in the most aggressive nodular-type tumors. Unlike MT1-MMP and MT2-MMP, which promote cell invasion through basement membranes and collagen type I-rich tissues, the function of MT3-MMP in tumor progression remains unclear. Here, we demonstrate that MT3-MMP inhibits MT1-MMP-driven melanoma cell invasion in three-dimensional collagen, while yielding an altered, yet MT1-MMP-dependent, form of expansive growth behavior that phenocopies the formation of nodular cell colonies. In melanoma cell lines originating from advanced primary or metastatic lesions, endogenous MT3-MMP expression was associated with limited collagen-invasive potential. In the cell lines with highest MT3-MMP expression relative to MT1-MMP, collagen-invasive activity was increased following stable MT3-MMP gene silencing. Consistently, MT3-MMP overexpression in cells derived from less advanced superficially spreading melanoma lesions, or in the MT3-MMP knockdown cells, reduced MT1-MMP-dependent collagen invasion. Rather than altering MT1-MMP transcription, MT3-MMP interacted with MT1-MMP in membrane complexes and reduced its cell surface expression. By contrast, as a potent fibrinolytic enzyme, MT3-MMP induced efficient invasion of the cells in fibrin, a provisional matrix component frequently found at tumor-host tissue interfaces and perivascular spaces of melanoma. Since MT3-MMP was significantly upregulated in biopsies of human melanoma metastases, these results identify MT3-MMP as a matrix-dependent modifier of the invasive tumor cell functions during melanoma progression.
authors.affiliation: Research Programs Unit, Molecular Cancer Biology, University of Helsinki, Helsinki, Finland.
authors.forename: Olga
authors.initials: O
authors.lastname: Tatti
authors.forename: Mariliina
authors.initials: M
authors.lastname: Arjama
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
authors.forename: Jorma
authors.initials: J
authors.lastname: Keski-Oja
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehti
mesh_terms: D002384:Catalysis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D018450:Disease Progression; D005337:Fibrin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008207:Lymphatic Metastasis; D053513:Matrix Metalloproteinase 16 / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D005337:Fibrin; D003094:Collagen; D053513:Matrix Metalloproteinase 16