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Br J Cancer. Feb 1999; 79(3-4): 377–385.
PMCID: PMC2362451
Inflammatory cell-mediated tumour progression and minisatellite mutation correlate with the decrease of antioxidative enzymes in murine fibrosarcoma cells
F Okada,1 K Nakai,1 T Kobayashi,1 T Shibata,2 S Tagami,3 Y Kawakami,3 T Kitazawa,4 R Kominami,4 S Yoshimura,5 K Suzuki,7 N Taniguchi,7 O Inanami,8 M Kuwabara,8 H Kishida,9 D Nakae,9 Y Konishi,9 T Moriuchi,6 and M Hosokawa1
Laboratory of Pathology, Cancer Institute, Sapporo, 060-8638, Japan
Department of Oral Surgery, Health Science, University of Hokkaido, Ishikari, 061-0293, Japan
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, 060-8638, Japan
First Department of Biochemistry, Niigata University School of Medicine, Niigata, 951-8510, Japan
Department of Molecular Life Science (Cell Biology), Tokai University School of Medicine, Isehara, 259-1193, Japan
Laboratory of Cell Biology, Hokkaido University School of Medicine, Sapporo, 060-8638, Japan
Department of Biochemistry, Osaka University Medical School, Osaka, 565-0871, Japan
Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Sapporo, 060-0818, Japan
Department of Oncological Pathology, Cancer Center, Kashihara, 634-8521, Japan
*Laboratory of Pathology, Cancer Institute, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan
Received January 9, 1998; Revised July 7, 1998; Accepted July 13, 1998.
Abstract
We isolated six clones of weakly tumorigenic fibrosarcoma (QR) from the tumorigenic clone BMT-11 cl-9. The QR clones were unable to grow in normal C57BL/6 mice when injected s.c. (1 × 105 cells). However, they formed aggressive tumours upon co-implantation with a ‘foreign body’, i.e. a gelatin sponge, and the rate of tumour take ranged from 8% to 58% among QR clones. The enhanced tumorigenicity was due to host cell-mediated reaction to the gelatin sponge (inflammation). Immunoblot analysis and enzyme activity assay revealed a significant inverse correlation between the frequencies of tumour formation by QR clones and the levels of manganese superoxide dismutase (Mn-SOD, P<0.005) and glutathione peroxidase (GPχ, P<0.01) in the respective tumour clones. Electron spin resonance (ESR) revealed that superoxide-scavenging ability of cell lysates of the QR clone with high level of Mn-SOD was significantly higher than that with low level of the antioxidative enzyme in the presence of potassium cyanide, an inhibitor for copper–zinc superoxide dismutase (CuZn-SOD) (P<0.001). Minisatellite mutation (MSM) induced by the inflammatory cells in tumour cells were investigated by DNA fingerprint analysis after QR clones had been co-cultured with gelatin-sponge-reactive cells. The MSM rate was significantly higher in the subclones with low levels of Mn-SOD and GPχ (P<0.05) than in the subclones with high levels of both enzymes. The MSM of the subclones with low levels of both enzymes was inhibited in the presence of mannitol, a hydroxyl radical scavenger. The content of 8-hydroxydeoxyguanosine (8-OHdG) by which the cellular DNA damage caused by active oxygen species can be assessed was significantly low in the tumours arising from the QR clone with high levels of Mn-SOD and GPχ even if the clone had been co-implanted with gelatin sponge, compared with the arising tumour from the QR clone with low levels of those antioxidative enzymes (P<0.001). In contrast, CuZn-SOD and catalase levels in the six QR clones did not have any correlation with tumour progression parameters. These results suggest that tumour progression is accelerated by inflammation-induced active oxygen species particularly accompanied with declined levels of intracellular antioxidative enzymes in tumour cells. © 1999 Cancer Research Campaign
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