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Membrane-type 1 matrix metalloprotease (MT1-MMP) enables invasive migration of glioma cells in central nervous system white matter.

Beliën AT, Paganetti PA, Schwab ME - J. Cell Biol. (1999)

Bottom Line: Plasma membranes of both MT1-MMP-transfected fibroblasts and C6 glioma cells inactivated inhibitory myelin extracts, and this activity was sensitive to the same protease inhibitors.Interestingly, pretreatment of CNS myelin with gelatinase A/MMP-2 could not inactivate its inhibitory property.These data imply an important role of MT1-MMP in spreading and migration of glioma cells on white matter constituents in vitro and point to a function of MT1-MMP in the invasive behavior of malignant gliomas in the CNS in vivo.

View Article: PubMed Central - PubMed

Affiliation: Brain Research Institute, University of Zurich and Swiss Federal Institute of Technology, 8057 Zurich, Switzerland. belien@hifo.unizh.ch

ABSTRACT
Invasive glioma cells migrate preferentially along central nervous system (CNS) white matter fiber tracts irrespective of the fact that CNS myelin contains proteins that inhibit cell migration and neurite outgrowth. Previous work has demonstrated that to migrate on a myelin substrate and to overcome its inhibitory effect, rat C6 and human glioblastoma cells require a membrane-bound metalloproteolytic activity (C6-MP) which shares several biochemical and pharmacological characteristics with MT1-MMP. We show now that MT1-MMP is expressed on the surface of rat C6 glioblastoma cells and is coenriched with C6-MP activity. Immunodepletion of C6-MP activity is achieved with an anti-MT1-MMP antibody. These data suggest that MT1-MMP and the C6-MP are closely related or identical. When mouse 3T3 fibroblasts were transfected with MT1-MMP they acquired the ability to spread and migrate on the nonpermissive myelin substrate and to infiltrate into adult rat optic nerve explants. MT1-MMP-transfected fibroblasts and C6 glioma cells were able to digest bNI-220, one of the most potent CNS myelin inhibitory proteins. Plasma membranes of both MT1-MMP-transfected fibroblasts and C6 glioma cells inactivated inhibitory myelin extracts, and this activity was sensitive to the same protease inhibitors. Interestingly, pretreatment of CNS myelin with gelatinase A/MMP-2 could not inactivate its inhibitory property. These data imply an important role of MT1-MMP in spreading and migration of glioma cells on white matter constituents in vitro and point to a function of MT1-MMP in the invasive behavior of malignant gliomas in the CNS in vivo.

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MT1-MMP immunoreactivity in C6 glioblastoma cells  and MT1-MMP–transfected fibroblasts 1 h after plating the cells  on CNS substrate. (a) Well-spread C6 cell shows diffuse MT1-MMP staining over the plasma membrane, especially along the  cell periphery. (b) When the plane of focus is at the level of the  substrate, MT1-MMP immunoreactivity is detected at the substrate contact sites. (c) MT1-MMP–transfected fibroblasts show  immunoreactivity enriched on lamellipodia (arrows). (d) 24 h after plating MT1-MMP–transfected fibroblasts cells formed long  processes on which foci of MT1-MMP are observed (arrowhead).  Bar, 14 μm.
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Figure 1: MT1-MMP immunoreactivity in C6 glioblastoma cells and MT1-MMP–transfected fibroblasts 1 h after plating the cells on CNS substrate. (a) Well-spread C6 cell shows diffuse MT1-MMP staining over the plasma membrane, especially along the cell periphery. (b) When the plane of focus is at the level of the substrate, MT1-MMP immunoreactivity is detected at the substrate contact sites. (c) MT1-MMP–transfected fibroblasts show immunoreactivity enriched on lamellipodia (arrows). (d) 24 h after plating MT1-MMP–transfected fibroblasts cells formed long processes on which foci of MT1-MMP are observed (arrowhead). Bar, 14 μm.

Mentions: To determine if MT1-MMP is expressed on the surface of C6 glioblastoma cells, cells were plated on a CNS inhibitory protein substrate for 1 h. The cells were firmly attached and well spread assuming the typical fried egg appearance. Immunofluorescence with a monoclonal anti– MT1-MMP antibody revealed staining along the plasma membrane (Fig. 1 a) often enriched at substrate contact sites (Fig. 1 b).


Membrane-type 1 matrix metalloprotease (MT1-MMP) enables invasive migration of glioma cells in central nervous system white matter.

Beliën AT, Paganetti PA, Schwab ME - J. Cell Biol. (1999)

MT1-MMP immunoreactivity in C6 glioblastoma cells  and MT1-MMP–transfected fibroblasts 1 h after plating the cells  on CNS substrate. (a) Well-spread C6 cell shows diffuse MT1-MMP staining over the plasma membrane, especially along the  cell periphery. (b) When the plane of focus is at the level of the  substrate, MT1-MMP immunoreactivity is detected at the substrate contact sites. (c) MT1-MMP–transfected fibroblasts show  immunoreactivity enriched on lamellipodia (arrows). (d) 24 h after plating MT1-MMP–transfected fibroblasts cells formed long  processes on which foci of MT1-MMP are observed (arrowhead).  Bar, 14 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2132902&req=5

Figure 1: MT1-MMP immunoreactivity in C6 glioblastoma cells and MT1-MMP–transfected fibroblasts 1 h after plating the cells on CNS substrate. (a) Well-spread C6 cell shows diffuse MT1-MMP staining over the plasma membrane, especially along the cell periphery. (b) When the plane of focus is at the level of the substrate, MT1-MMP immunoreactivity is detected at the substrate contact sites. (c) MT1-MMP–transfected fibroblasts show immunoreactivity enriched on lamellipodia (arrows). (d) 24 h after plating MT1-MMP–transfected fibroblasts cells formed long processes on which foci of MT1-MMP are observed (arrowhead). Bar, 14 μm.
Mentions: To determine if MT1-MMP is expressed on the surface of C6 glioblastoma cells, cells were plated on a CNS inhibitory protein substrate for 1 h. The cells were firmly attached and well spread assuming the typical fried egg appearance. Immunofluorescence with a monoclonal anti– MT1-MMP antibody revealed staining along the plasma membrane (Fig. 1 a) often enriched at substrate contact sites (Fig. 1 b).

Bottom Line: Plasma membranes of both MT1-MMP-transfected fibroblasts and C6 glioma cells inactivated inhibitory myelin extracts, and this activity was sensitive to the same protease inhibitors.Interestingly, pretreatment of CNS myelin with gelatinase A/MMP-2 could not inactivate its inhibitory property.These data imply an important role of MT1-MMP in spreading and migration of glioma cells on white matter constituents in vitro and point to a function of MT1-MMP in the invasive behavior of malignant gliomas in the CNS in vivo.

View Article: PubMed Central - PubMed

Affiliation: Brain Research Institute, University of Zurich and Swiss Federal Institute of Technology, 8057 Zurich, Switzerland. belien@hifo.unizh.ch

ABSTRACT
Invasive glioma cells migrate preferentially along central nervous system (CNS) white matter fiber tracts irrespective of the fact that CNS myelin contains proteins that inhibit cell migration and neurite outgrowth. Previous work has demonstrated that to migrate on a myelin substrate and to overcome its inhibitory effect, rat C6 and human glioblastoma cells require a membrane-bound metalloproteolytic activity (C6-MP) which shares several biochemical and pharmacological characteristics with MT1-MMP. We show now that MT1-MMP is expressed on the surface of rat C6 glioblastoma cells and is coenriched with C6-MP activity. Immunodepletion of C6-MP activity is achieved with an anti-MT1-MMP antibody. These data suggest that MT1-MMP and the C6-MP are closely related or identical. When mouse 3T3 fibroblasts were transfected with MT1-MMP they acquired the ability to spread and migrate on the nonpermissive myelin substrate and to infiltrate into adult rat optic nerve explants. MT1-MMP-transfected fibroblasts and C6 glioma cells were able to digest bNI-220, one of the most potent CNS myelin inhibitory proteins. Plasma membranes of both MT1-MMP-transfected fibroblasts and C6 glioma cells inactivated inhibitory myelin extracts, and this activity was sensitive to the same protease inhibitors. Interestingly, pretreatment of CNS myelin with gelatinase A/MMP-2 could not inactivate its inhibitory property. These data imply an important role of MT1-MMP in spreading and migration of glioma cells on white matter constituents in vitro and point to a function of MT1-MMP in the invasive behavior of malignant gliomas in the CNS in vivo.

Show MeSH
Related in: MedlinePlus