Inhibition of glioblastoma angiogenesis and invasion by combined treatments directed against vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and vascular endothelial-cadherin
Inhibition of glioblastoma angiogenesis and invasion by combined treatments directed against vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and vascular endothelial-cadherin
复制标题
DOI：
10.1158/1078-0432.ccr-04-2270
复制
发表时间：
2005-07-01
影响因子：
11.5
通讯作者：
Westphal, M
中科院分区：
文献类型：
--
作者：
Lamszus, K;Brockmann, MA;Westphal, M
目的：抑制血管生成可影响肿瘤细胞的侵袭和转移。我们以前的研究表明，用单克隆抗体DC 101阻断血管内皮生长因子受体-2（VEGFR-2）可抑制脑内胶质母细胞瘤的生长，但会增加肿瘤细胞沿原有血管系统的沿着浸润。在本研究中，我们试图抑制胶质瘤细胞的侵袭使用单克隆抗体对表皮生长因子受体（EGFR），在人类胶质母细胞瘤的情况下，已牵连在肿瘤细胞的侵袭。此外，我们分析了阻断血管内皮（VE）-钙粘蛋白作为不同的抗血管生成靶点是否也能抑制胶质母细胞瘤血管生成和生长。实验设计：接受脑内胶质母细胞瘤异种移植的裸鼠单独或不同组合使用抗VEGFR-2（DC 101）、EGFR（C225）和VE-钙粘蛋白（E4 G10）的单克隆抗体进行治疗。由DC 101单药治疗引起的肿瘤细胞侵袭增加被C225和DC 101联合治疗抑制50%至66%。C225在体外抑制胶质母细胞瘤细胞迁移，但在体内对主要肿瘤块的体积或肿瘤细胞增殖或凋亡没有影响，无论是单独还是与DC 101组合。抗VE-钙粘蛋白单克隆抗体E4 G10是一个较弱的肿瘤血管生成和生长的抑制剂比DC 101，也造成了较弱的增加，在肿瘤细胞invasion.Conclusions：抑制血管生成实现阻断VEGFR-2或VE-钙粘蛋白可以导致增加胶质瘤细胞的侵袭原位模型。DC 101有效抑制血管生成诱导的肿瘤细胞侵袭增加可以通过同时阻断EGFR来抑制。
Purpose: Inhibition of angiogenesis can influence tumor cell invasion and metastasis. We previously showed that blockade of vascular endothelial growth factor receptor-2 (VEGFR-2) with the monoclonal antibody DC101 inhibited intracerebral glioblastoma growth but caused increased tumor cell invasion along the preexistent vasculature. In the present study, we attempted to inhibit glioma cell invasion using a monoclonal antibody against the epidermal growth factor receptor (EGFR), which in the context of human glioblastomas, has been implicated in tumor cell invasion. In addition, we analyzed whether blockade of vascular endothelial (VE)-cadherin as a different antiangiogenic target could also inhibit glioblastoma angiogenesis and growth.Experimental Designs: Nude mice who received intracerebral glioblastoma xenografts were treated using monoclonal antibodies against VEGFR-2 (DC101), EGFR (C225), and VE-cadherin (E4G10) either alone or in different combinations.Results: Increased tumor cell invasion provoked by DC101 monotherapy was inhibited by 50% to 66% by combined treatment with C225 and DC101. C225 inhibited glioblastoma cell migration in vitro, but had no effect on the volume of the main tumor mass or on tumor cell proliferation or apoptosis in vivo, either alone or in combination with DC101. The anti-VE-cadherin monoclonal antibody E4G10 was a weaker inhibitor of tumor angiogenesis and growth than DC101, and also caused a weaker increase in tumor cell invasion.Conclusions: Inhibition of angiogenesis achieved by blocking either VEGFR-2 or VE-cadherin can cause increased glioma cell invasion in an orthotopic model. Increased tumor cell invasion induced by potent inhibition of angiogenesis with DC101 could be inhibited by simultaneous blockade of EGFR.