Malignant gliomas infiltrate the brain preferentially along myelinated fiber tracts. Central nervous system (CNS) myelin, however, contains inhibitory proteins that block axon regeneration, neurite outgrowth, and cell spreading of astrocytes and fibroblasts. We tested 5 human brain tumor cell lines, 1 rat brain tumor cell line, and 29 short-term cultured specimens from human brain tumors for their ability to spread and migrate on a CNS myelin substrate. Low-grade and pilocytic astrocytoma, ependymoma, medulloblastoma, and meningioma cell lines as well as primary cultures were strongly sensitive to the inhibitory proteins present in the CNS myelin. In contrast, glioblastomas, anaplastic astrocytomas, 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 correlated with the grade of malignancy of the original tumor. Cell spreading of glioblastomas and anaplastic astrocytomas specifically on a CNS myelin substrate was strongly inhibited by the metalloprotease blocker O-phenanthroline and the peptide derivative carbobenzoxy-Phe-Ala-Phe-Tyr-amide, whereas blockers for serine, aspartyl, and cysteine proteases had no effect. Enzymatic peptide degradation assays revealed the presence of a phosphoramidon-sensitive and thiorphan-insensitive metalloproteolytic 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.
Supported by the Swiss National Science Foundation Grants 31-29981.90 and 31-45549.95, the Hartman-Müller Foundation (Zurich, Switzerland), and Regeneron Pharmaceuticals, Inc. (Tarrytown, NY). V. R. A. and T. H. contributed equally to this work.