[Induction of manganese superoxide dismutase by an immunopotentiator as a mechanism of inhibiting of malignant progression of murine tumor cells].
A weakly tumorigenic cell clone (QR-32) derived from a murine fibrosarcoma (BMT-11) grew lethally in 6 out of 10 syngeneic C57BL/6 mice after co-implantation with gelatin sponge. All six cell lines (QRsP) established from the arising tumors from QR-32 had enhanced tumorigenicity and/or pulmonary metastatic ability in vivo, indicating that those QRsP cell lines acquired progressed phenotypes as compared with those of QR-32 cells. In contrast, the frequency of tumor progression was suppressed to 50% (3/6) in the cell lines (QRsP/PSK) established from those arising in the mice treated with an immunopotentiating protein-bound polysaccharide, PSK. The enhanced metastatic ability was accompanied by enhanced expressions of a tumor-associated transcription factor, E1AF and by increased production of matrix metalloproteinase (MMP) in five lines of QRsP and two lines of QRsP/PSK. It was found that administration of PSK augmented the production of an antioxidative enzyme, manganese superoxide dismutase (Mn-SOD), in the tumor tissues co-implanted with gelatin sponge. PSK administration also brought about up-regulation of interferon-gamma (IFN-gamma)-expression and down-regulation of transforming growth factor-beta (TGF-beta)-expression in the tumor tissues, which were examined by RT-PCR on day 7, 14 and 21 after the co-implantation. Other inflammatory cytokines such as interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) were expressed equally both in PSK-treated and untreated tumor tissues. In vitro experiments proved that although IFN-gamma did not increase the production of Mn-SOD by itself, concomitant treatment with both IFN-gamma and TNF-alpha enhanced the Mn-SOD-production in QR-32 cells greatly. On the contrary, TGF-beta treatment lowered the Mn-SOD level in QR-32 cells. PSK-treatment did not induce Mn-SOD in cultured QR-32 cells directly. These results indicated that PSK inhibits the malignant progression of QR-32 cells promoted by co-implantation with gelatin sponge, most possibly through elevating the Mn-SOD level in QR-32 cells via modulation of the production of inflammatory cytokines, that is, increasing IFN-gamma and decreasing TGF-beta at the site of tumor growth.
Habelhah
H
H
Laboratory of Pathology, Hokkaido University School of Medicine, Sapporo, Japan.
D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005780:Gelatin; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D011509:Proteoglycans / Q000494:pharmacology* / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017500:Adenovirus E1A Proteins; D000276:Adjuvants, Immunologic; D016207:Cytokines; D011509:Proteoglycans; D014157:Transcription Factors; C010770:polysaccharide-K; D005780:Gelatin; D013482:Superoxide Dismutase; D008666:Metalloendopeptidases