Adenoviral-mediated gene transduction of the hepatocyte growth factor (HGF) antagonist, NK4, suppresses peritoneal metastases of gastric cancer in nude mice.
Adenoviral-mediated gene transduction of the hepatocyte growth factor (HGF) antagonist, NK4, suppresses peritoneal metastases of gastric cancer in nude mice.
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DOI：
10.1016/j.ejca.2004.05.006
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发表时间：
2004-09
影响因子：
8.4
通讯作者：
K. Ueda;M. Iwahashi;I. Matsuura;M. Nakamori;Masaki Nakamura;T. Ojima;T. Naka;Koichiro Ishida;Kunio Matsumoto;Toshikazu Nakamura;H. Yamaue
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作者：
K. Ueda;M. Iwahashi;I. Matsuura;M. Nakamori;Masaki Nakamura;T. Ojima;T. Naka;Koichiro Ishida;Kunio Matsumoto;Toshikazu Nakamura;H. Yamaue
NK 4（一种特异性肝细胞生长因子（HGF）拮抗剂）对HGF和c-Met/HGF受体之间相互作用的竞争性抑制作用已在HGF介导的某些不同类型的人类癌细胞的侵袭中显示。此外，NK 4对由碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF）以及HGF驱动的血管生成途径具有抑制作用。在这项研究中，评估腺病毒介导的NK 4基因治疗的治疗效果，我们采用腹膜转移的动物模型，使用两种胃癌细胞系，强c-Met表达的MKN 45细胞系和弱c-Met表达的细胞系，TMK 1。在两种模型中，与用磷酸盐缓冲溶液（PBS）和AxCALacZ处理的那些相比，用AxCANK 4（在肿瘤接种后2、7和12天施用3次）早期处理的每只小鼠的腹膜肿瘤和腹水的总数和重量显著减少（P<0.05）。在来自腹膜转移性肿瘤的因子VIII相关抗原染色切片中，在来自用AxCANK 4处理的MKN 45和TMK 1肿瘤的组织中观察到肿瘤内血管的抑制。我们还比较了早期AxCANK 4治疗与晚期治疗（第7、12和17天）的治疗效果。在两种模型中，晚期用AxCANK 4治疗的腹膜转移和腹水显示出比早期用AxCANK 4治疗的改善更少。此外，顺铂（CDDP）对腹膜转移的抑制作用被AxCANK 4显著增强，表明腹膜内（i. p.）NK 4基因治疗的化疗可能是有效的，即使在晚期胃癌腹膜转移的情况下。总之，这些结果清楚地表明，NK 4基因治疗抑制胃癌腹膜转移，无论肿瘤细胞中c-Met/HGF受体表达水平如何，尤其是在腹膜转移的早期阶段。
The competitive inhibitory effects of NK4 (a specific hepatocyte growth factor (HGF)-antagonist) on the interaction between HGF and the c-Met/HGF receptor has been shown in HGF-mediated invasion of some distinct types of human cancer cells. Furthermore, NK4 has inhibitory effects on the angiogenic pathways driven by basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), as well as by HGF. In this study, to evaluate the therapeutic efficacy of adenoviral-mediated NK4 gene treatment, we employed animal models of peritoneal metastasis using two gastric cancer cell lines, the strongly c-Met expressing MKN45 cell line and the weakly c-Met-expressing cell line, TMK1. In both models, the total number and weight of peritoneal tumours per mouse and ascites treated early with AxCANK4 (administered 3 times 2, 7 and 12 days after the tumour inoculation) were significantly reduced compared with those treated with phosphate-buffered solution (PBS) and AxCALacZ (P<0.05). In Factor-VIII-related-antigen-stained sections from peritoneal metastatic tumours, the inhibition of intratumour vessels was observed in tissues from tumours of MKN45 and TMK1 treated with AxCANK4. We also compared the therapeutic effect of early AxCANK4 treatment with that of late treatment (at 7, 12 and 17 days). Peritoneal metastases and ascites treated late with AxCANK4 showed less of an improvement than those treated early with AxCANK4 in both models. In addition, the inhibitory effect of cisplatin (CDDP) on peritoneal metastasis was significantly enhanced by AxCANK4, suggesting that the combination of intraperitoneal (i.p.) chemotherapy with NK4 gene therapy might be effective, even in cases of advanced peritoneal metastasis from gastric cancer. To conclude, these results show clearly that NK4 gene therapy inhibits peritoneal metastases from gastric cancer, regardless of the level of c-Met/HGF receptor expression in the tumour cells, and especially in the early stages of peritoneal metastasis.