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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–transfected fibroblasts infiltrated the optic nerves over longer distances than mock-transfected fibroblasts. Values are means ± SEM of 12 nerves infiltrated with  MT1-MMP–transfected fibroblasts, 12 nerves with mock-transfected fibroblasts, and eight nerves with C6 cells. Significance  with the two-tailed Student's t test: P < 0.01 (**).
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Figure 10: MT1-MMP–transfected fibroblasts infiltrated the optic nerves over longer distances than mock-transfected fibroblasts. Values are means ± SEM of 12 nerves infiltrated with MT1-MMP–transfected fibroblasts, 12 nerves with mock-transfected fibroblasts, and eight nerves with C6 cells. Significance with the two-tailed Student's t test: P < 0.01 (**).

Mentions: Pairs of adult rat optic nerves were cultured in a three-compartment chamber culture and Hoechst dye-labeled cells were placed at one end of the nerve explants (Fig. 9 a). After 7 d in vitro the distance of cell infiltration was evaluated on longitudinal histological sections. Mock-transfected fibroblasts did not infiltrate the CNS explants for more than 0.8 mm. In contrast, large numbers of the MT1-MMP–transfected fibroblasts infiltrated over 1–1.6 mm into the optic nerve, distances very similar to those seen with C6 glioblastoma cells (Fig 9, b–d). Quantification and distance of fibroblast infiltration is shown in Fig. 10. MT1-MMP expression thus enables fibroblasts to infiltrate this adult CNS tissue rich in myelin.


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–transfected fibroblasts infiltrated the optic nerves over longer distances than mock-transfected fibroblasts. Values are means ± SEM of 12 nerves infiltrated with  MT1-MMP–transfected fibroblasts, 12 nerves with mock-transfected fibroblasts, and eight nerves with C6 cells. Significance  with the two-tailed Student's t test: P < 0.01 (**).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 10: MT1-MMP–transfected fibroblasts infiltrated the optic nerves over longer distances than mock-transfected fibroblasts. Values are means ± SEM of 12 nerves infiltrated with MT1-MMP–transfected fibroblasts, 12 nerves with mock-transfected fibroblasts, and eight nerves with C6 cells. Significance with the two-tailed Student's t test: P < 0.01 (**).
Mentions: Pairs of adult rat optic nerves were cultured in a three-compartment chamber culture and Hoechst dye-labeled cells were placed at one end of the nerve explants (Fig. 9 a). After 7 d in vitro the distance of cell infiltration was evaluated on longitudinal histological sections. Mock-transfected fibroblasts did not infiltrate the CNS explants for more than 0.8 mm. In contrast, large numbers of the MT1-MMP–transfected fibroblasts infiltrated over 1–1.6 mm into the optic nerve, distances very similar to those seen with C6 glioblastoma cells (Fig 9, b–d). Quantification and distance of fibroblast infiltration is shown in Fig. 10. MT1-MMP expression thus enables fibroblasts to infiltrate this adult CNS tissue rich in myelin.

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