Futakuchi Mitsuru, Ogawa Kumiko, Sano Masashi, Tamano Seiko, Takeshita Fumitaka, Shirai Tomoyuki
Department of Experimental Pathology, Graduate School of Medical Science, Nagoya City University, and Nagoya-shi Kohseiin Geriatric Hospital, Nagoya, Japan.
Jpn J Cancer Res. 2002 Oct;93(10):1175-81. doi: 10.1111/j.1349-7006.2002.tb01220.x.
To examine the effect of non-steroidal anti-inflammatory drugs on metastasis formation, aspirin (ASP, 0.5% in diet) and indomethacin (IM, 0.005% in drinking water) were applied to an in vivo highly metastatic rat hepatocellular carcinoma (HCC) model in F344 male rats. Administration for 8 weeks after induction of highly metastatic HCC by sequential treatment with diethylnitrosamine and N-nitrosomorpholine did not cause any significant change in survival rate or body weight. Multiplicity of HCC in the liver increased during ASP or IM treatment without any significant histological alteration. Although absent in the rats killed at the end of the period of carcinogen exposure, lung metastasis at the end of the experiment was found in 100%, 89% and 100% of rats in the control, ASP and IM groups, respectively. Degree of metastasis was classified into three groups according to the number of metastatic nodules, i.e., slight (1 - 5 nodules), moderate (6 - 50) and severe (more than 51), which amounted to 0%, 43% and 57% in the control group. ASP significantly reduced the degree of metastasis, the incidences being 33%, 44%, and 11%, respectively, whereas IM was without significant influence. Both agents suppressed cell proliferation in HCCs, without any alteration of pan-cadherin expression. However, expression in HCC of mRNAs for intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, both of which are considered to play key roles in attachment of cancer cells to the endothelium, was significantly suppressed by ASP. Thus, the present study demonstrated that ASP, but not IM, has the potential to inhibit lung metastasis of rat HCC in vivo, possibly via reduced attachment of tumor cells to the vascular endothelium. Moreover, these data indicate this in vivo model for induction of rat highly metastatic HCC to be a useful tool for the assessment of the efficacy of therapeutic treatments to block metastasis formation.
为研究非甾体抗炎药对转移形成的影响，将阿司匹林（ASP，饲料中含量0.5%）和吲哚美辛（IM，饮用水中含量0.005%）应用于F344雄性大鼠体内高转移性大鼠肝细胞癌（HCC）模型。在用二乙基亚硝胺和N-亚硝基吗啉序贯处理诱导高转移性HCC后给药8周，未引起存活率或体重的任何显著变化。在ASP或IM处理期间，肝脏中HCC的数量增加，而无任何显著的组织学改变。虽然在致癌物暴露期结束时处死的大鼠中未发现肺转移，但在实验结束时，对照组、ASP组和IM组大鼠的肺转移率分别为100%、89%和100%。根据转移结节数量将转移程度分为三组，即轻度（1 - 5个结节）、中度（6 - 50个）和重度（超过51个），对照组分别为0%、43%和57%。ASP显著降低了转移程度，发生率分别为33%、44%和11%，而IM无显著影响。两种药物均抑制HCC中的细胞增殖，而不改变泛钙黏蛋白的表达。然而，细胞间黏附分子-1和血管细胞黏附分子-1的mRNA在HCC中的表达，这两者均被认为在癌细胞与内皮细胞的黏附中起关键作用，被ASP显著抑制。因此，本研究表明，ASP而非IM有可能在体内抑制大鼠HCC的肺转移，可能是通过减少肿瘤细胞与血管内皮的黏附。此外，这些数据表明，这种诱导大鼠高转移性HCC的体内模型是评估阻断转移形成的治疗方法疗效的有用工具。
