TY - JOUR
T1 - Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP
AU - Sabeh, Farideh
AU - Ota, Ichiro
AU - Holmbeck, Kenn
AU - Birkedal-Hansen, Henning
AU - Soloway, Paul
AU - Balbin, Milagros
AU - Lopez-Otin, Carlos
AU - Shapiro, Steven
AU - Inada, Masaki
AU - Krane, Stephen
AU - Allen, Edward
AU - Chung, Duane
AU - Weiss, Stephen J
PY - 2004/11/22
Y1 - 2004/11/22
N2 - 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.
AB - 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.
KW - Animals
KW - Cell Membrane/metabolism
KW - Cell Movement/genetics
KW - Cells, Cultured
KW - Chick Embryo
KW - Coculture Techniques
KW - Collagen/metabolism
KW - Collagenases/metabolism
KW - Extracellular Matrix/metabolism
KW - Fibroblasts/cytology
KW - Gene Targeting
KW - Matrix Metalloproteinase 13
KW - Matrix Metalloproteinase 14
KW - Matrix Metalloproteinase 2/metabolism
KW - Matrix Metalloproteinase 3/metabolism
KW - Matrix Metalloproteinase 9/metabolism
KW - Matrix Metalloproteinases, Membrane-Associated
KW - Metalloendopeptidases/genetics
KW - Mice
KW - Mice, Knockout
KW - Neoplasm Invasiveness
KW - Neoplasms/enzymology
KW - Phenotype
U2 - 10.1083/jcb.200408028
DO - 10.1083/jcb.200408028
M3 - Journal article
C2 - 15557125
SN - 0021-9525
VL - 167
SP - 769
EP - 781
JO - The Journal of Cell Biology
JF - The Journal of Cell Biology
IS - 4
ER -