Habelhah H
Laboratory of Pathology, Hokkaido University School of Medicine, Sapporo, Japan.
Hokkaido Igaku Zasshi. 1998 Sep;73(5):519-29.
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.
从鼠纤维肉瘤（BMT - 11）衍生出的弱致瘤性细胞克隆（QR - 32），在与明胶海绵共同植入后，10只同基因C57BL / 6小鼠中有6只因肿瘤生长而死亡。从QR - 32产生的肿瘤中建立的所有6个细胞系（QRsP）在体内均具有增强的致瘤性和/或肺转移能力，这表明与QR - 32细胞相比，那些QRsP细胞系获得了进展期表型。相反，在用免疫增强性蛋白结合多糖PSK处理的小鼠中产生的肿瘤所建立的细胞系（QRsP/PSK）中，肿瘤进展频率被抑制至50%（3/6）。在5个QRsP细胞系和2个QRsP/PSK细胞系中，转移能力增强伴随着肿瘤相关转录因子E1AF表达增强以及基质金属蛋白酶（MMP）产生增加。研究发现，给予PSK可增加与明胶海绵共同植入的肿瘤组织中抗氧化酶锰超氧化物歧化酶（Mn - SOD）的产生。在共同植入后第7、14和21天通过RT - PCR检测发现，给予PSK还导致肿瘤组织中干扰素 - γ（IFN - γ）表达上调以及转化生长因子 - β（TGF - β）表达下调。其他炎性细胞因子如白细胞介素 - 1α（IL - 1α）和肿瘤坏死因子 - α（TNF - α）在PSK处理和未处理的肿瘤组织中表达相当。体外实验证明，虽然IFN - γ本身不会增加Mn - SOD的产生，但IFN - γ和TNF - α联合处理可显著增强QR - 32细胞中Mn - SOD的产生。相反，TGF - β处理会降低QR - 32细胞中Mn - SOD水平。PSK处理在培养的QR - 32细胞中不会直接诱导Mn - SOD产生。这些结果表明，PSK抑制了与明胶海绵共同植入所促进的QR - 32细胞的恶性进展，最有可能是通过调节炎性细胞因子的产生来提高QR - 32细胞中的Mn - SOD水平，即在肿瘤生长部位增加IFN - γ并减少TGF - β。
