Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase
Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase
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DOI：
10.1158/1078-0432.ccr-07-5270
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发表时间：
2008-09-01
影响因子：
11.5
通讯作者：
Asada, Makoto
中科院分区：
文献类型：
--
作者：
Matsui, Junji;Funahashi, Yasuhiro;Asada, Makoto
目的：血管内皮生长因子（VEGF）-C/VEGF受体3（VEGF-R3）信号通过对淋巴管的作用在淋巴管生成和肿瘤转移中起重要作用。然而，关于使用小分子激酶抑制剂抑制VEGF-R3对淋巴管生成和淋巴结转移的影响知之甚少。我们评估了E7080的作用，E7080是VEGF-R2和VEGF-R3激酶的有效抑制剂，和贝伐单抗对人乳腺癌的乳腺脂肪垫异种移植物模型中的淋巴管生成和血管生成的影响。231个表达过量VEGF-C的细胞。结果：MDA-MB-435细胞VEGF表达量与MDA-MB-231细胞相似，但VEGF-C表达量低于MDA-MB-231细胞，而MDA-MB-231细胞仅在原发肿瘤中出现淋巴管生成。E7080而不是贝伐单抗显著降低了MDA-MB-231肿瘤内的LVD。在MDA-MB-231和MDA-MB-435模型中，E7080和贝伐珠单抗均降低了MVD。E7080显著抑制MDA-MB-231的局部淋巴结和远处肺转移，而贝伐单抗仅显著抑制肺转移。E7080还降低了原发肿瘤切除后淋巴结转移结节内的MVD和LVD。结论：用E7080抑制VEGF-133激酶可有效降低表达VEGF-C的MDA-MB-231肿瘤内的LVD。同时抑制VEGF-R2和VEGF-R3激酶的E7080可能是一个有前途的新策略，以控制区域淋巴结和远处肺转移。
Purpose: Vascular endothelial growth factor (VEGF)-C/VEGF-receptor 3 (VEGF-R3) signal plays a significant role in lymphangiogenesis and tumor metastasis based on its effects on lymphatic vessels. However, little is known about the effect of inhibiting VEGF-R3 on lymphangiogenesis and lymph node metastases using a small-molecule kinase inhibitor.Experimental Design: We evaluated the effect of E7080, a potent inhibitor of both VEGF-R2 and VEGF-R3 kinase, and bevacizumab on lymphangiogenesis and angiogenesis in a mammary fat pad xenograft model of human breast cancer using MDA-MB-231 cells that express excessive amounts of VEGF-C. Lymphangiogenesis was determined by lymphatic vessel density (LVD) and angiogenesis by microvessel density (MVD).Results: In contrast to MDA-MB-435 cells, which expressed a similar amount of VEGF to MDA-MB-231 cells with an undetectable amount of VEGF-C, only MDA-MB-231 exhibited lymphangiogenesis in the primary tumor. E7080 but not bevacizumab significantly decreased LVD within the MDA-MB-231 tumor. E7080 and bevacizumab decreased MVD in both the MDA-MB-231 and MDA-MB-435 models. E7080 significantly suppressed regional lymph nodes and distant lung metastases of MDA-MB-231, whereas bevacizumab significantly inhibited only lung metastases. E7080 also decreased both MVD and LVD within the metastatic nodules at lymph nodes after resection of the primary tumor.Conclusions: Inhibition of VEGF-133 kinase with E7080 effectively decreased LVD within MDA-MB-231 tumors, which express VEGF-C. Simultaneous inhibition of both VEGF-R2 and VEGF-R3 kinases by E7080 may be a promising new strategy to control regional lymph node and distant lung metastases.