Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells
Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells
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DOI：
10.1002/ijc.25976
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发表时间：
2012-01-01
影响因子：
6.4
通讯作者：
Hida, Kyoko
中科院分区：
文献类型：
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作者：
Muraki, Chikara;Ohga, Noritaka;Hida, Kyoko
肿瘤血管生成对于实体瘤的进展和转移是必需的。环加氧酶 (COX)-2 已知在癌症生长和侵袭中发挥重要作用，它激活控制细胞增殖、迁移、凋亡和血管生成的信号通路。据报道，COX-2 在许多癌细胞中表达。几项研究报告了用 COX-2 抑制剂 (COX-2is) 成功治疗癌细胞。然而，COX-2抑制对肿瘤内皮的影响仍有待阐明。我们的研究表明，COX-2 在手术切除的人类肿瘤的脉管系统中表达。为了在体外研究 COX-2 抑制对肿瘤内皮的影响，我们从人类黑色素瘤和小鼠口腔癌异种移植物中分离出肿瘤内皮细胞 (TEC)，并证实 COX-2is NS398 通过抑制血管生成来抑制肿瘤生长。与正常内皮细胞 (NEC) 相比，TEC 中 COX-2 mRNA 上调。 NS398 在 TEC 中抑制细胞迁移和增殖，但在 NEC 中则不然。 NS398的体内作用与体外结果一致。 COX-2抑制显着抑制循环中CD133(+)/血管内皮生长因子受体-2(+)细胞的数量。此外，COX-2i治疗后肿瘤血管中祖细胞标志物阳性细胞的数量减少，这表明祖细胞归巢到肿瘤中也被阻断。我们得出结论，NS398 特异性靶向 TEC 和血管祖细胞，而不影响 NEC。
Tumor angiogenesis is necessary for solid tumor progression and metastasis. Cyclooxygenase (COX)-2 is known to play an important role in cancer growth and invasion, and it activates the signaling pathways controlling cell proliferation, migration, apoptosis, and angiogenesis. COX-2 is reported to be expressed in many cancer cells. Several studies have reported successful treatment of cancer cells with COX-2 inhibitors (COX-2is). However, the effect of COX-2 inhibition on the tumor endothelium remains to be elucidated. Our study shows that COX-2 is expressed in the vasculature of surgically resected human tumors. To investigate the effects of COX-2 inhibition on the tumor endothelium in vitro, we isolated tumor endothelial cells (TECs) from human melanoma and oral carcinoma xenografts in mice, in which we confirmed that tumor growth was suppressed by inhibiting angiogenesis with the COX-2is NS398. COX-2 mRNA was upregulated in TECs compared to normal endothelial cells (NECs). Cell migration and proliferation were suppressed by NS398 in TECs but not in NECs. The effects of NS398 in vivo were consistent with the in vitro results. The number of CD133(+)/vascular endothelial growth factor receptor-2(+) cells in circulation was significantly suppressed by COX-2 inhibition. In addition, the number of progenitor marker-positive cells decreased in the tumor blood vessels after COX-2i treatment, which suggests that the homing of progenitor cells into the tumor was also blocked. We conclude that NS398 specifically targets both TECs and vascular progenitor cells without affecting NECs.