Liu Huidong, Yang Yanmei, Xiao Jianbing, Lv Yanhong, Liu Yan, Yang Huike, Zhao Linghui
Department of Anatomy, Harbin Medical University, Harbin, China.
Anat Rec (Hoboken). 2009 Oct;292(10):1577-83. doi: 10.1002/ar.20940.
Most experimental work addressing cyclooxygenase-2 (COX-2) inhibitor has focused on suppressing hematogenic spread. Little is known about the mechanism by which this inhibitor can also block lymphatic metastasis. Here, the effects of COX-2 inhibitor on vascular endothelial growth factor-C (VEGF-C) expression, lymphangiogenesis and lymph node metastasis were investigated. Utilizing the highly metastatic human lung adenocarcinoma cell line Anip973 and its parental line AGZY83-a, which has a low metastatic capacity, we found elevated VEGF-C and COX-2 immunoreactivity in Anip973 cells compared with AGZY83-a cells. Celecoxib down-regulated expression of VEGF-C mRNA and protein in Anip973 cells while PGE(2) up-regulated expression of VEGF-C mRNA and protein in AGZY83-a cells in a concentration-dependent manner. The expression of COX-2 and VEGF-C was significantly increased in xenografted Anip973 tumors compared with AGZY83-a tumors. The Anip973 tumors showed more lymphatic vessels and lymph node metastasis than the AGZY83-a tumors. In vivo, celecoxib decreased VEGF-C expression in Anip973 tumor-treated mice to a similar level to that in the AGZY83-a tumor-treated mice. Consistent with this decrease in VEGF-C expression, the density of lymphatic vessels and lymph node metastasis in Anip973 tumor-treated mice were suppressed to approximately that found in the AGZY83-a tumor-treated ones. Taken together, our results suggest that the differential expression of COX-2 and VEGF-C might help explain the different metastasis phenotype of lung adenocarcinoma cancer, and that COX-2 inhibitor mediates VEGF-C to block lymphangiogenesis and lymph node metastasis. Thus, COX-2 may be a potential therapeutic target for blocking lymph node metastasis in lung adenocarcinoma.
大多数针对环氧化酶-2（COX-2）抑制剂的实验研究都集中在抑制血行转移上。对于这种抑制剂还能阻断淋巴转移的机制，人们了解甚少。在此，研究了COX-2抑制剂对血管内皮生长因子-C（VEGF-C）表达、淋巴管生成和淋巴结转移的影响。利用高转移性的人肺腺癌细胞系Anip973及其低转移能力的亲本细胞系AGZY83-a，我们发现与AGZY83-a细胞相比，Anip973细胞中VEGF-C和COX-2免疫反应性升高。塞来昔布下调了Anip973细胞中VEGF-C mRNA和蛋白的表达，而前列腺素E2（PGE2）以浓度依赖性方式上调了AGZY83-a细胞中VEGF-C mRNA和蛋白的表达。与AGZY83-a肿瘤相比，异种移植的Anip973肿瘤中COX-2和VEGF-C的表达显著增加。Anip973肿瘤比AGZY83-a肿瘤显示出更多的淋巴管和淋巴结转移。在体内，塞来昔布将Anip973肿瘤治疗小鼠中的VEGF-C表达降低到与AGZY83-a肿瘤治疗小鼠相似的水平。与VEGF-C表达的这种降低一致，Anip973肿瘤治疗小鼠中的淋巴管密度和淋巴结转移被抑制到与AGZY83-a肿瘤治疗小鼠中大致相同的水平。综上所述，我们的结果表明，COX-2和VEGF-C的差异表达可能有助于解释肺腺癌不同的转移表型，并且COX-2抑制剂通过介导VEGF-C来阻断淋巴管生成和淋巴结转移。因此，COX-2可能是阻断肺腺癌淋巴结转移的潜在治疗靶点。
