Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice
Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice
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DOI：
10.1136/gut.2005.067900
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发表时间：
2005-07
期刊：
影响因子：
24.5
通讯作者：
H. Yoshiji;S. Kuriyama;R. Noguchi;J. Yoshii;Y. Ikenaka;K. Yanase;T. Namisaki;Mitsuteru Kitade;M. Uemura;Tsutomu Masaki;Hiroshi Fukui
中科院分区：
文献类型：
--
作者：
H. Yoshiji;S. Kuriyama;R. Noguchi;J. Yoshii;Y. Ikenaka;K. Yanase;T. Namisaki;Mitsuteru Kitade;M. Uemura;Tsutomu Masaki;Hiroshi Fukui
背景资料：两大类血管生成因子--即血管内皮生长因子（VEGF）和血管生成素2（Ang-2）--的表达已被证明在肿瘤血管生成（包括肝细胞癌（HCC））中起关键作用。然而，很少有研究集中在这些因素在体内肿瘤的发展和血管生成的直接相互作用。目的：研究两种因子在小鼠肝癌中的相互作用。研究方法：我们通过在饮用水中提供四环素逆转录病毒（泰特）调节的体内基因操作系统和常规质粒基因表达系统的组合，研究了VEGF和Ang-2过表达的组合效应。结果：Ang-2和VEGF过表达均不能诱导肝癌细胞增殖。在体内，尽管Ang-2的过表达并没有增加肿瘤的发展，但Ang-2和VEGF的同时表达协同增强了小鼠肝癌中的肿瘤生长和血管生成。Ang-2加VEGF诱导的肿瘤发展显着衰减治疗与中和单克隆抗体抗VEGF受体。Ang-2和VEGF过表达显著增加肿瘤中基质金属蛋白酶（MMP）-2和MMP-9的活性。抑制瘤内VEGF几乎完全取消了这种增强的MMPs。结论：这些结果表明，Ang-2协同增强VEGF介导的HCC发展和血管生成。这种促血管生成活性仅在VEGF存在下发挥，至少部分通过诱导肿瘤中的MMP-2和MMP-9介导。
Background: Orchestration of two major classes of angiogenic factors—namely, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2)—has been shown to play a pivotal role in tumour angiogenesis, including hepatocellular carcinoma (HCC). However, few studies have focused on the direct interaction of these factors on in vivo tumour development and angiogenesis. Aim: To examine the interaction between both factors in murine HCC. Methods: We examined the combination effect of VEGF and Ang-2 overexpression by means of a combination of a retroviral tetracycline (tet) regulated gene manipulating system in vivo, by providing tet in the drinking water, and a conventional plasmid gene expression system. Results: Neither Ang-2 nor VEGF overexpression induced proliferation of HCC cells in vitro. In vivo, although overexpression of Ang-2 did not increase tumour development, simultaneous expression of Ang-2 and VEGF synergistically augmented tumour growth and angiogenesis in murine HCC. Ang-2 plus VEGF induced tumour development was markedly attenuated by treatment with neutralising monoclonal antibodies against VEGF receptors. Ang-2 plus VEGF overexpression significantly increased the activities of matrix metalloproteinase (MMP)-2 and MMP-9 in the tumour. Suppression of intratumoral VEGF almost completely abolished this augmentation of MMPs. Conclusions: These results suggest that Ang-2 synergistically augments VEGF mediated HCC development and angiogenesis. This proangiogenic activity was exerted only in the presence of VEGF, at least partly mediated via induction of MMP-2 and MMP-9 in the tumour.