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.
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22 November 2004
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November 22 2004
Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP
Farideh Sabeh,
Farideh Sabeh
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
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Ichiro Ota,
Ichiro Ota
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
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Kenn Holmbeck,
Kenn Holmbeck
2National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
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Henning Birkedal-Hansen,
Henning Birkedal-Hansen
2National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
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Paul Soloway,
Paul Soloway
3College of Human Ecology, Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853
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Milagros Balbin,
Milagros Balbin
4Departamento de Bioquimica, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006 Oviedo, Spain
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Carlos Lopez-Otin,
Carlos Lopez-Otin
4Departamento de Bioquimica, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006 Oviedo, Spain
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Steven Shapiro,
Steven Shapiro
5Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
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Masaki Inada,
Masaki Inada
5Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
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Stephen Krane,
Stephen Krane
5Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
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Edward Allen,
Edward Allen
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
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Duane Chung,
Duane Chung
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
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Stephen J. Weiss
Stephen J. Weiss
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
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Farideh Sabeh
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
Ichiro Ota
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
Kenn Holmbeck
2National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
Henning Birkedal-Hansen
2National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
Paul Soloway
3College of Human Ecology, Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853
Milagros Balbin
4Departamento de Bioquimica, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006 Oviedo, Spain
Carlos Lopez-Otin
4Departamento de Bioquimica, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006 Oviedo, Spain
Steven Shapiro
5Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
Masaki Inada
5Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
Stephen Krane
5Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
Edward Allen
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
Duane Chung
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
Stephen J. Weiss
1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
Correspondence to Stephen J. Weiss: [email protected]
Abbreviations used in this paper: CAM, chicken chorioallantoic membrane; HGF, hepatocyte growth factor; MMP, matrix metalloproteinase.
Received:
August 04 2004
Accepted:
September 23 2004
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2004
J Cell Biol (2004) 167 (4): 769–781.
Article history
Received:
August 04 2004
Accepted:
September 23 2004
Citation
Farideh Sabeh, Ichiro Ota, Kenn Holmbeck, Henning Birkedal-Hansen, Paul Soloway, Milagros Balbin, Carlos Lopez-Otin, Steven Shapiro, Masaki Inada, Stephen Krane, Edward Allen, Duane Chung, Stephen J. Weiss; Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP . J Cell Biol 22 November 2004; 167 (4): 769–781. doi: https://doi.org/10.1083/jcb.200408028
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