A metalloprotease activity from C6 glioma cells inactivates the myelin-associated neurite growth inhibitors and can be neutralized by antibodies

Glioblastoma cells infiltrate brain tissue and migrate preferentially along white matter fibre tracts, an environment that is highly inhibitory to the migration of astrocytes and the growth of neurites because of the presence of specific inhibitory proteins. In vitro, spreading and migration of rat C6 glioma cells on a CNS (central nervous system) myelin substrate is corre lated with and dependent on the presence of a metalloprotease. This membran e-bound metalloendoprotease exhibits a blocker profile different from known proteases. Pretreatment of CNS myelin or of a highly purified GNS myelin c omponent,the inhibitory protein bNI-220, with C6 metalloproteolytic activit y converts these non-permissive substrates into permissive environments for astrocytes and fibroblasts, indicating that this C6 cell-derived metallopr otease may inactivate myelin-associated inhibitory proteins. Antibodies wer e raised in chicken against fractions enriched in metalloproteolytic activi ty; these antibodies were able to inhibit specifically spreading and migrat ion of C6 glioma cells on a CNS myelin substrate, as well as the invasion o f C6 cells into adult rat optic nerve explants in vitro. These results sugg est a crucial involvement of a membrane-bound metalloprotease in the mechan isms of C6 glioma migration and infiltration of brain tissue by proteolytic inactivation of the neurite growth inhibitory proteins present in CMS myel in.