Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3

During tissue-invasive events, migrating cells penetrate type I collagen-ri ch interstitial tissues by mobilizing undefined proteolytic enzymes. To scr een for members of the matrix metalloproteinase (MMP) family that mediate c ollagen-invasive activity, an in vitro model system was developed wherein M DCK cells were stably transfected to overexpress each of ten different MMPs that have been linked to matrix remodeling states. MDCK cells were then st imulated with scatter factor/hepatocyte growth factor (SF/HGF) to initiate invasion and tubulogenesis atop either type I collagen or interstitial stro ma to determine the ability of MMPs to accelerate, modify, or disrupt morph ogenic responses. Neither secreted collagenases (MMP-1 and MMP-13), gelatin ases (gelatinase A or B), stromelysins (MMP-3 and MMP-11), or matrilysin (M MP-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 direct ly confer invasion-incompetent cells with the ability to penetrate type I c ollagen matrices. MT-MMP-dependent invasion proceeded independently of proM MP-2 activation, but required the enzymes to be membrane-anchored to the ce ll surface. These findings demonstrate that MT-MMP-expressing cells can pen etrate and remodel type I collagen-rich tissues by using membrane-anchored metalloproteinases as pericellular collagenases.