Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis
Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis
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DOI：
10.1158/0008-5472.can-07-2366
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发表时间：
2007-11-01
期刊：
影响因子：
11.2
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
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作者：
Iwata, Caname;Kano, Mitsunobu R.;Miyazono, Kohei
环氧合酶-2（考克斯-2）抑制剂已被报道可抑制肿瘤进展。然而，目前还不清楚这种抑制剂是否也可以预防淋巴转移。为了确定考克斯-2抑制剂对淋巴转移的影响，口服给予考克斯-2抑制剂依托度酸。对具有原位异种移植物或具有用高转移性人弥漫型胃癌细胞系OCUM-2 MLN诱导的癌性腹膜炎的小鼠。依托度酸处理的小鼠与对照小鼠相比，肿瘤淋巴管生成显著减少。与淋巴管生成减少一致，依托度酸处理小鼠的转移性淋巴结总重量低于对照小鼠。免疫组化分析显示，在我们的模型中，血管内皮生长因子-C（VEGF-C）和VEGF-D的主要来源是F4/80阳性的巨噬细胞。依托度酸可抑制小鼠巨噬细胞样RAW264.7细胞及肿瘤组织中VEGF-C的mRNA水平。依托度酸对人真皮淋巴管微血管内皮细胞的生长也有抑制作用。依托度酸还抑制慢性无菌性腹膜炎模型中的淋巴管生成，这表明考克斯-2在没有癌细胞的情况下可以增强淋巴管生成，这支持了这些发现。我们的研究结果表明，考克斯-2抑制剂可能是有用的，通过减少巨噬细胞介导的肿瘤淋巴管生成的淋巴结转移的预防。
Cyclooxygenase-2 (COX-2) inhibitor has been reported to suppress tumor progression. However, it is unclear whether this inhibitor can also prevent lymphatic metastasis. To determine the effects of COX-2 inhibitor on lymphatic metastasis, etodolac, a COX-2 inhibitor, was given p.o. to mice bearing orthotopic xenografts or with carcinomatous peritonitis induced with a highly metastatic human diffuse-type gastric carcinoma cell line, OCUM-2MLN. Tumor lymphangiogenesis was significantly decreased in etodolac-treated mice compared with control mice. Consistent with this decrease in lymphangiogenesis, the total weight of metastatic lymph nodes was less in etodolac-treated mice than in control mice. Immunohistochemical analysis revealed that the major source of vascular endothelial growth factor-C (VEGF-C) and VEGF-D was F4/80-positive macrophages in our models. The mRNA levels of VEGF-C in mouse macrophage-like RAW264.7 cells, as well as those in tumor tissues, were suppressed by etodolac. The growth of human dermal lymphatic microvascular endothelial cells was also suppressed by etodolac. Supporting these findings, etodolac also inhibited lymphangiogenesis in a model of chronic aseptic peritonitis, suggesting that COX-2 can enhance lymphangiogenesis in the absence of cancer cells. Our findings suggest that COX-2 inhibitor may be useful for prophylaxis of lymph node metastasis by reducing macrophage-mediated tumor lymphangiogenesis.