Regulation of Cell Invasion and Morphogenesis in a Three-Dimensional Type I Collagen Matrix by Membrane-Type Matrix Metalloproteinases 1, 2, and 3

By K. Hotary, E. Allen, A. Punturieri, I. Yana, S. Weiss. Journal of Cell Biology, 2000

624 citations recorded by the source corpus.

During tissue-invasive events, migrating cells penetrate type I collagen-rich interstitial tissues by mobilizing undefined proteolytic enzymes. To screen for members of the matrix metalloproteinase (MMP) family that mediate collagen-invasive activity, an in vitro model system was developed wherein MDCK cells were stably transfected to overexpress each of ten different MMPs that have been linked to matrix remodeling states. MDCK cells were then stimulated with scatter factor/hepatocyte growth factor (SF/HGF) to initiate invasion and tubulogenesis atop either type I collagen or interstitial stroma to determine the ability of MMPs to accelerate, modify, or disrupt morphogenic responses. Neither secreted collagenases (MMP-1 and MMP-13), gelatinases (gelatinase A or B), stromelysins (MMP-3 and MMP-11), or matrilysin (MMP-7) affected SF/HGF-induced responses. By contrast, the membrane-anchored metalloproteinases, membrane-type 1 MMP, membrane-type 2 MMP, and membrane-type 3 MMP (MT1-, MT2-, and MT3-MMP) each modified the morphogenic program. Of the three MT-MMPs tested, only MT1-MMP and MT2-MMP were able to directly confer invasion-incompetent cells with the ability to penetrate type I collagen matrices. MT-MMP–dependent invasion proceeded independently of proMMP-2 activation, but required the enzymes to be membrane-anchored to the cell surface. These findings demonstrate that MT-MMP–expressing cells can penetrate and remodel type I collagen-rich tissues by using membrane-anchored metalloproteinases as pericellular collagenases.

Subfields: Cancer Research, Hematology

View Paper: https://www.semanticscholar.org/paper/9362b288d924a6f269196de57eca2d48d571fd6e

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Citations in the corpus

Building epithelial architecture: insights from three-dimensional culture models (2002, background): “Indeed, overexpression of MT1-MMP confers invasive behaviour to MDCK cells in the absence of HGF, whereas overexpression of soluble MMPs does no”
Extracellular matrix remodelling: the role of matrix metalloproteinases (2003, background): “MT-MMPs have been shown to localize to invadopodia — specialized plasma membrane protrusions believed to constitute the cellular structures that direct invasion [29,30] — and to lose their proteolytic activity when expressed in secreted form [29,31].”
Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP (2004, methodology): “Invasion assays Type I collagen was acid or pepsin extracted from rat or mice tail tendons (Birkedal-Hansen, 1987; Hotary et al., 2000).”
How matrix metalloproteinases regulate cell behavior. (2001, background): “Removal of the transmembrane domains of MT1, MT2, and MT3MMP abolishes their ability to promote cellular invasion (Hotary et al. 2000).”
The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function (2011, neutral): “Similar MMP-dependent protrusive structures have been seen in 3D cultures of SRC-transformed mouse sarcomas, and human melanoma, fibrosarcoma and breast cancer cell”