title: Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP.
abstract: As cancer cells traverse collagen-rich extracellular matrix (ECM) barriers and intravasate, they adopt a fibroblast-like phenotype and engage undefined proteolytic cascades that mediate invasive activity. Herein, we find that fibroblasts and cancer cells express an indistinguishable pericellular collagenolytic activity that allows them to traverse the ECM. Using fibroblasts isolated from gene-targeted mice, a matrix metalloproteinase (MMP)-dependent activity is identified that drives invasion independently of plasminogen, the gelatinase A/TIMP-2 axis, gelatinase B, collagenase-3, collagenase-2, or stromelysin-1. In contrast, deleting or suppressing expression of the membrane-tethered MMP, MT1-MMP, in fibroblasts or tumor cells results in a loss of collagenolytic and invasive activity in vitro or in vivo. Thus, MT1-MMP serves as the major cell-associated proteinase necessary to confer normal or neoplastic cells with invasive activity.
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Farideh
authors.initials: F
authors.lastname: Sabeh
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ota
authors.forename: Kenn
authors.initials: K
authors.lastname: Holmbeck
authors.forename: Henning
authors.initials: H
authors.lastname: Birkedal-Hansen
authors.forename: Paul
authors.initials: P
authors.lastname: Soloway
authors.forename: Milagros
authors.initials: M
authors.lastname: Balbin
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Otin
authors.forename: Steven
authors.initials: S
authors.lastname: Shapiro
authors.forename: Masaki
authors.initials: M
authors.lastname: Inada
authors.forename: Stephen
authors.initials: S
authors.lastname: Krane
authors.forename: Edward
authors.initials: E
authors.lastname: Allen
authors.forename: Duane
authors.initials: D
authors.lastname: Chung
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D002642:Chick Embryo; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D018390:Gene Targeting; D053509:Matrix Metalloproteinase 13; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D010641:Phenotype
chemical_list: C507096:Mmp14 protein, mouse; D003094:Collagen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C507081:Mmp13 protein, mouse; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14