SPREADING AND MIGRATION OF HUMAN GLIOMA AND RAT C6 CELLS ON CENTRAL-NERVOUS-SYSTEM MYELIN IN-VITRO IS CORRELATED WITH TUMOR MALIGNANCY AND INVOLVES A METALLOPROTEOLYTIC ACTIVITY

Malignant gliomas infiltrate the brain preferentially along myelinated tiber tracts. Central nervous system (CNS) myelin, however, contains inhibitory proteins that block axon regeneration, neurite outgrowth, a nd cell spreading of astrocytes and fibroblasts, We tested 5 human bra in tumor cell lines, 1 rat brain tumor cell line, and 29 short-term cu ltured specimens from human brain tumors for their ability to spread a nd migrate on a CNS myelin substrate. Low-grade and pilocytic astrocyt oma, ependymoma, medulloblastoma, and meningioma cell lines as well as primary cultures were strongly sensitive to the inhibitory proteins p resent in the CNS myelin. In contrast, glioblastomas, anaplastic astro cytomas, and oligodendrogliomas were able to spread and migrate on CNS myelin-coated culture dishes, demonstrating that within the gliomas, the ability to overcome the inhibitory effects of the CNS myelin is co rrelated with the grade of malignancy of the original tumor, Cell spre ading of glioblastomas and anaplastic astrocytomas specifically on a C NS myelin substrate was strongly inhibited by the metalloprotease bloc ker O-phenanthroline and the peptide derivative carbobenzoxy-Phe-Ala-P he-Tyr-amide, whereas blockers for serine, aspartyl, and cysteine prot eases had no effect. Enzymatic peptide degradation assays revealed the presence of a phosphor-amidon-sensitive and thiorphan-insensitive met alloproteolytic activity in the plasma membranes of high-grade glioma cells. These results suggest a crucial involvement of a membrane-bound metalloendoprotease in the process of invasive migration of malignant gliomas along CNS white matter fiber tracts.