PT  - JOURNAL ARTICLE
AU  - H Yoshiji
AU  - S Kuriyama
AU  - R Noguchi
AU  - J Yoshii
AU  - Y Ikenaka
AU  - K Yanase
AU  - T Namisaki
AU  - M Kitade
AU  - M Uemura
AU  - T Masaki
AU  - H Fukui
TI  - Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice
AID  - 10.1136/gut.2005.067900
DP  - 2005 Dec 01
TA  - Gut
PG  - 1768--1775
VI  - 54
IP  - 12
4099  - http://gut.bmj.com/content/54/12/1768.short
4100  - http://gut.bmj.com/content/54/12/1768.full
SO  - Gut2005 Dec 01; 54
AB  - 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.