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Published 22 November 2004. doi:10.1083/jcb.200408028
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 4, 769-781
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Article

Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP



Farideh Sabeh1, Ichiro Ota1, Kenn Holmbeck2, Henning Birkedal-Hansen2, Paul Soloway3, Milagros Balbin4, Carlos Lopez-Otin4, Steven Shapiro5, Masaki Inada5, Stephen Krane5, Edward Allen1, Duane Chung1, and Stephen J. Weiss1

1 Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
2 National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
3 College of Human Ecology, Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853
4 Departamento de Bioquimica, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006 Oviedo, Spain
5 Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114

Correspondence to Stephen J. Weiss: sjweiss{at}umich.edu

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.

Abbreviations used in this paper: CAM, chicken chorioallantoic membrane; HGF, hepatocyte growth factor; MMP, matrix metalloproteinase.


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