Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis.
Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis.
复制标题
DOI：
10.1186/1471-2407-10-641
复制
发表时间：
2010-11-23
期刊：
影响因子：
3.8
通讯作者：
Duarte A
中科院分区：
文献类型：
--
作者：
Djokovic D;Trindade A;Gigante J;Badenes M;Silva L;Liu R;Li X;Gong M;Krasnoperov V;Gill PS;Duarte A
Dll4/Notch和Ephrin - B2/EphB4通路在肿瘤血管生成和成熟过程中发挥关键作用。本研究评估了单独及联合抑制这两种信号通路在减少原位小鼠肿瘤生长方面的效果，并评估了潜在的不良反应。
我们使用转基因RIP1 - Tag2肿瘤模型来研究以下情况的影响：1）通过Dll4等位基因缺失或使用可溶性细胞外Dll4（sDll4）抑制Dll4/Notch；2）通过与白蛋白融合的可溶性细胞外EphB4（sEphB4 - Alb）抑制Ephrin - B2/EphB4信号传导；3）通过sEphB4 - Alb与Dll4等位基因缺失或sDll4联合抑制两种通路。为了研究不良反应，我们使用诱导性内皮特异性Dll4敲除小鼠，用sEphB4 - Alb进行处理，并进行组织病理学分析。
Dll4等位基因缺失或可溶性Dll4处理导致肿瘤血管密度增加、血管壁细胞募集减少以及血管灌注减少，从而使肿瘤体积缩小。可溶性EphB4则降低了血管密度和血管灌注，导致肿瘤体积减小。当sEphB4 - Alb与Dll4等位基因缺失或sDll4联合使用时，在肿瘤大小、血管灌注和血管壁细胞募集方面观察到了更强的效果。诱导性内皮特异性Dll4功能缺失导致肝脏血管改变，而同时使用sEphB4 - Alb治疗可预防这种改变。
联合靶向Dll4/Notch和Ephrin - B2/EphB4具有临床研究的潜力，相较于单独抑制Dll4/Notch具有累积疗效且安全性更高。
Dll4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects. We used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of Dll4/Notch by either Dll4 allelic deletion or use of a soluble extracellular Dll4 (sDll4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either Dll4 allelic deletion or sDll4. To investigate adverse effects, we used inducible endothelial-specific Dll4 knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis. Dll4 allele deletion or soluble Dll4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either Dll4 allele deletion or sDll4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific Dll4 loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment. Combination targeting of Dll4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over Dll4/Notch inhibition alone.
登录
查看更多内容
影响因子：
16
作者：
Gerety, SS;Wang, HU;Anderson, DJ
通讯作者：
Anderson, DJ
影响因子：
15.9
作者：
Abramsson, A;Lindblom, P;Betsholtz, C
通讯作者：
Betsholtz, C
影响因子：
11.2
作者：
Patel, NS;Li, JL;Harris, AL
通讯作者：
Harris, AL
影响因子：
64.8
作者：
HANAHAN, D
通讯作者：
HANAHAN, D
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--