Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth.
Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth.
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DOI：
10.1158/0008-5472.can-09-1977
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
McDonald DM
中科院分区：
文献类型：
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作者：
Hashizume H;Falcón BL;Kuroda T;Baluk P;Coxon A;Yu D;Bready JV;Oliner JD;McDonald DM
抑制血管生成素-2(Ang2)可以减缓肿瘤的生长，但其潜在机制尚不完全清楚。由于Ang2在生长中的血管中表达，并在血管内皮生长因子(VEGF)的驱动下促进血管生成，因此我们询问Ang2抑制的抗肿瘤作用是否源于减少发芽的血管生成，以及是否通过抑制肿瘤细胞中的VEGF来增强这种作用。以Colo205人结肠癌裸鼠模型为研究对象，发现多肽-Fc融合蛋白L1-7(N)选择性抑制Ang2，26天后血管萌发数减少46%，肿瘤生长减少62%。值得注意的是，当Ang2抑制剂与功能阻断的抗血管内皮生长因子抗体联合使用时，与对照组相比，萌芽数量减少了82%，肿瘤血管减少了67%，肿瘤生长速度减缓了91%。肿瘤生长减慢的同时伴随着细胞增殖减少和细胞凋亡增加。我们的结论是，抑制Ang2通过抑制血管生成来限制肿瘤血管的扩张，从而减缓肿瘤的生长，同时抑制血管内皮生长因子，并导致肿瘤细胞的增殖减少和凋亡增加。
Inhibition of angiopoietin-2 (Ang2) can slow tumor growth, but the underlying mechanism is not fully understood. Because Ang2 is expressed in growing blood vessels and promotes angiogenesis driven by vascular endothelial growth factor (VEGF), we asked whether the anti-tumor effect of Ang2 inhibition results from reduced sprouting angiogenesis and whether the effect is augmented by inhibition of VEGF from tumor cells. Using Colo205 human colon carcinomas in nude mice as a model, we found that selective inhibition of Ang2 by the peptide-Fc fusion protein L1-7(N) reduced the number of vascular sprouts by 46% and tumor growth by 62% over 26 days. Strikingly, when the Ang2 inhibitor was combined with a function-blocking anti-VEGF antibody, the number of sprouts was reduced by 82%, tumor vascularity was reduced by 67%, and tumor growth slowed by 91% compared to controls. The reduction in tumor growth was accompanied by decreased cell proliferation and increased apoptosis. We conclude that inhibition of Ang2 slows tumor growth by limiting the expansion of the tumor vasculature by sprouting angiogenesis, in a manner that is complemented by concurrent inhibition of VEGF and leads to reduced proliferation and increased apoptosis of tumor cells.