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Glioblastoma Infiltration Into Central Nervous System Tissue in Vitro: Involvement of a Metalloprotease Paolo A

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Glioblastoma Infiltration Into Central Nervous System Tissue in Vitro: Involvement of a Metalloprotease Paolo A Glioblastoma Infiltration into Central Nervous System Tissue in Vitro: Involvement of a Metalloprotease Paolo A. Paganetti, Pico Caroni, and Martin E. Schwab Brain Research Institute of the University of Zurich, CH-8029 Zurich, Switzerland Abstract. Differentiated oligodendrocytes and central fibroblasts or B16 melanomas. Specific blockers of the nervous system (CNS) myelin are nonpermissive sub- serine, cysteine, and aspartyl protease classes had no strates for neurite growth and for cell attachment and effect. C6 cell spreading on inhibitor-free substrates spreading. This property is due to the presence of such as CNS gray matter, peripheral nervous system membrane-bound inhibitory proteins of 35 and 250 kD myelin, glass, or poly-D-lysine was not sensitive to and is specifically neutralized by monoclonal antibody 1,10-phenanthroline. IN-1 (Caroni, P., and M. E. Schwab. 1988. Neuron. The nonpermissive substrate properties of CNS my- 1:85-96). Using rat optic nerve explants, CNS frozen elin were strongly reduced by incubation with a sections, cultured oligodendrocytes or CNS myelin, we plasma membrane fraction prepared from C6 cells. show here that highly invasive CNS tumor line (C6 This reduction was sensitive to the same inhibitors of glioblastoma) was not inhibited by these myelin- metalloproteases. In our in vitro model for CNS white associated inhibitory components. Lack of inhibition matter invasion, cell infiltration of optic nerve ex- was due to a specific mechanism as the metalloenzyme plants, which occurred with C6 cells but not with 3T3 blocker 1,10-phenanthroline and two synthetic dipep- fibroblasts or B16 melanomas, was impaired by the tides containing metalloprotease-blocking sequences presence of the metalloprotease blockers. These results (gly-phe, tyr-tyr) specifically impaired C6 cell spread- suggest that C6 cell infiltrative behavior in CNS white ing on CNS myelin. In the presence of these inhibi- matter in vitro occurs by means of a metalloproteolytic tors, C6 cells were affected by the IN-l-sensitive inhib- activity, which probably acts on the myelin-associated itors in the same manner as control cells, e.g., 3T3 inhibitory substrates. N the normal adult central nervous system (CNS) t cell mechanisms allowing this infiltrative behavior in the CNS mobility is extremely restricted and nerve fiber growth tissue have not been elucidated so far. Of particular interest I or regeneration over distances of >1 mm is almost ab- is the interaction of the tumor cells with the myelin-asso- sent. Several factors may contribute to this situation, which ciated inhibitory substrate components, which have been is so different from that in most peripheral organs: the blood- shown in vitro to inhibit not only nerve fiber growth but also brain barrier restricting access of blood-borne ceils to the fibroblast attachment and spreading (Caroni and Schwab, CNS; the very dense nature of CNS tissue; and the presence 1988a). of specific inhibitors for neurite growth and cell mobility. In vivo, detailed cell biological analysis is difficult because Such inhibitory constituents have been recently found as of the heterogeneity of most tumors and the complex local specific membrane proteins in the cell membranes of one tissue, vascular, and inflammatory reactions that occur type of CNS glial cells, the oligodendrocytes, and in their (Mork et al., 1984). In vitro models successfully reproduc- product, myelin (Caroni and Schwab, 1988a; Schwab and ing the inhibitory microenvironment of CNS white matter Caroni, 1988). They probably play an important role in the with regard to neurite growth and cell attachment have re- lack of regenerative neurite growth in the CNS of higher ver- cently been described (Schwab and Thoenen, 1985; Schwab tebrates. and Caroni, 1988; Savio and Schwab, 1988). In the present In the case of malignant, invasive CNS tumors (mainly study we used as a model the rat C6 glioblastoma line (Benda glioblastomas) infltration of grey and white matter areas et al., 1968), which is known to rapidly infiltrate CNS tissue of the CNS is observed (Mork et al., 1984). The specific in vivo (Auer et al., 1981; Yoshida et al., 1986). For the study of cell attachment and spreading, C6 cells were confronted with cultured oligodendrocytes, myelin, and purified neurite 1. Abbreviations used in this paper: Cbz, benzyloxycarbonyl; cm, carboxy- growth inhibitors. For the study of cell migration and infiltra- methyl; CNS, central nervous system; PLYS, poly-D-lysine; PNS, periph- tion, C6 cells were added to CNS frozen sections and optic eral nervous system; TIMP, tissue inhibitor of metalloproteases. nerve explants. Our results point to the crucial role of a © The Rockefeller University Press, 0021-9525/88/12/2281/11 $2.00 The Journal of Cell Biology, Volume 107, (No. 6, Pt. 1) Dec. 1988 2281-2291 2281 membrane-associated metaUoprotease for C6 motility in CNS C6 Plasma Membranes and Conditioned white matter in all these experimental paradigms. Medium Preparation C6 cells grown to 80% confluency were washed twice with Hanks medium, and harvested in 20 ml 8.5% sucrose, 50 mM NaC1, 10 mM Tris buf- Materials and Methods fer, pH 7.4 using a rubber policeman. After mechanical homogenization through a series of needles of decreasing size, a low purity plasma mem- brane fraction was obtained by centrifugation (5 min at 3,000 g, 10 rain at Cell Cultures 8,000 g, and then 2 h at 100,000 g). A higher purity fraction was isolated Rat C6, mouse NIH 3T3, and B16 cells were cultured in DME, sup- by loading the material on a discontinuous sucrose gradient, containing 50 plemented with 10% FCS, usually to, at most, 70-80% confluency. Cells mM NaC1, 10 mM Tris, pH 7.4 (Qnigley, 1976). 20-40% sucrose inter- were harvested with a short trypsin treatment (0.1% in Ca2+/Mg2+-frec phase (C6 plasma membranes fraction) and 40-60% sucrose interphase (C6 Hanks medium for 90 s), stopped by addition of FCS in excess, followed mitochondrial fraction) were collected, washed in Hank's medium, and by centrifugation (1,000 rpm, 6 rain). Cells were resuspended in either resuspended in MEMct. DME/FCS or defined serum-free medium (MEMct) and used for the experi- Conditioned media were obtained by cultivating 80% confluent C6 cell ments. Dissociated rat CNS glial cells were prepared starting from optic cultures for 1 d in MEMct. The medium was then collected and centrifuged nerves of 6-7-d-old Lewis rats as described (schwab and Caroni, 1988) and for 10 min at 3,000 g. In some experiments the conditioned medium was plated into poly-o-lysine (PLYS)-coated wells (100 mm 2, 100 lxl medium) concentrated 10 times using Centricon 10 microconcentrators (model Centri- at a density of 20000 cells per well. The culture medium was an enriched con 10, Amicon Corp., Danvers, MA). L15 medium with 5% rat serum, penicillin, and streptomycin. C6, 3T3, and B16 cells were added to 2-d-old cultures at a concentration of 30000 cells Treatment of CNS Myelin with C6 Plasma Membranes per well, incubated for 2 h, and fixed with warm 4 % formalin in 0.1 M phos- phate buffer, pH 7.4, 5% sucrose. Inhibitory oligodendrocytes were iden- CNS myelin-coated PLYS wells were prepared as described in the previous tiffed by double labeling using the specific antibodies 01 and 04 (Sommer section, but instead of being immediately tested as substrate, they were first and Schachner, 1981; Schwab and Caroni, 1988). incubated with 50 ~tl of C6 plasma membranes (containing 0.8 mg pm- tein/ml MEMct) at 37°C for 30 rain. Dishes were then rinsed twice with Hank's medium and immediately used as substrates for 3T3 cells. In some Preparation of Nerve Explants for Infiltration Assay experiments protease blockers were added to the membranes using 10 x so- lutions. Optic nerve and sciatic nerve explants were prepared as described (Schwab and Thoenen, 1985). Briefly, the nerves were rapidly dissected from ,x,8- wk-old male rats, cleaned from the meninges, frozen and thawed three times Results using liquid nitrogen, and placed under a teflon ring (13 mm ditto, 1 mm thick) sealed to a culture dish with silicon grease. Tw~ chambers connected only by the explants were obtained this way. 300,000 C6, 3T3, or BI6 cells C6 GIioblastomas but Not 3T3 b'ibroblasts were plated in the inner chamber in DME/FCS and incubated for 5-20 d. or B16 Melanomas Infiltrate Optic Nerve and The medium was changed every other day. Cultures were fixed overnight CNS White Matter In Vitro with 4% formalin. The nerve explants were mounted with Tissue-Tek (Reictaert-Jung, Nnssloch, Federal Republic of Germany); 10-154tm sec- Frozen optic nerve and sciatic nerve explants were placed tions were cut in a cryostat and collected on gelatine-coated coverslips. Af- under a teflon ring and sealed with silicon grease (Schwab ter drying at room temperature overnight the sections were stained in 0.75 % and Thoenen, 1985). C6 or 3T3 cells were plated into the cresyl violet, and evaluated. We counted the infiltrated cells starting from ring, in contact with one end of the nerve explants. Culture the tip of the nerves at which they were added. Each point represents the numbers of infiltrated cells per 0.7 Itm. Only the most central part of the medium was exchanged every other day, and after 5-20 d of nerves was considered (0.25 nun), where the explants presented the best incubation the nerves were fixed, and sectioned with a cryo- histology. Inhibition experiments were performed with nerve explants previ- tome. Infiltrated cells were recognized by cresyl violet stain- ously injected from both sides with 2 ttl of 3 mM cbz-tyr-tyr or cbz-ala-phe ing.
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