Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP.
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.
Sabeh
Farideh
F
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Ota
Ichiro
I
Holmbeck
Kenn
K
Birkedal-Hansen
Henning
H
Soloway
Paul
P
Balbin
Milagros
M
Lopez-Otin
Carlos
C
Shapiro
Steven
S
Inada
Masaki
M
Krane
Stephen
S
Allen
Edward
E
Chung
Duane
D
Weiss
Stephen J
SJ
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
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