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多激酶抑制剂E7080通过抑制血管内皮生长因子受体(VEGF-R)2和VEGF-R3激酶来抑制人乳腺肿瘤MDA-MB-231的淋巴结和肺转移。

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.

作者信息

Matsui Junji, Funahashi Yasuhiro, Uenaka Toshimitsu, Watanabe Tatsuo, Tsuruoka Akihiko, Asada Makoto

机构信息

Discovery Research Laboratories II, Eisai Co. Ltd., Tokodai, Tsukuba, Ibaraki Japan.

出版信息

Clin Cancer Res. 2008 Sep 1;14(17):5459-65. doi: 10.1158/1078-0432.CCR-07-5270.

Abstract

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-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.

摘要

目的

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。

实验设计

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。

结果

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。

结论

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。

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