Matsui Junji, Funahashi Yasuhiro, Uenaka Toshimitsu, Watanabe Tatsuo, Tsuruoka Akihiko, Asada Makoto
Discovery Research Laboratories II, Eisai Co. Ltd., Tokodai, Tsukuba, Ibaraki Japan.
Clin Cancer Res. 2008 Sep 1;14(17):5459-65. doi: 10.1158/1078-0432.CCR-07-5270.
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.
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).
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.
Inhibition of VEGF-R3 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.
血管内皮生长因子(VEGF)-C/VEGF受体3(VEGF-R3)信号基于其对淋巴管的作用,在淋巴管生成和肿瘤转移中发挥重要作用。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,目前所知甚少。
我们使用表达过量VEGF-C的MDA-MB-231细胞,在人乳腺癌的乳腺脂肪垫异种移植模型中,评估了VEGF-R2和VEGF-R3激酶的强效抑制剂E7080以及贝伐单抗对淋巴管生成和血管生成的影响。通过淋巴管密度(LVD)测定淋巴管生成,通过微血管密度(MVD)测定血管生成。
与MDA-MB-435细胞相比,MDA-MB-435细胞表达的VEGF量与MDA-MB-231细胞相似,但VEGF-C量无法检测到,只有MDA-MB-231在原发性肿瘤中表现出淋巴管生成。E7080而非贝伐单抗显著降低了MDA-MB-231肿瘤内的LVD。E7080和贝伐单抗在MDA-MB-231和MDA-MB-435模型中均降低了MVD。E7080显著抑制了MDA-MB-231的区域淋巴结和远处肺转移,而贝伐单抗仅显著抑制肺转移。E7080还降低了原发性肿瘤切除后淋巴结转移结节内的MVD和LVD。
用E7080抑制VEGF-R3激酶可有效降低表达VEGF-C的MDA-MB-231肿瘤内的LVD。E7080同时抑制VEGF-R2和VEGF-R3激酶可能是控制区域淋巴结和远处肺转移的一种有前景的新策略。