Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice.
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.


OBJECTIVE
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.
Yoshiji
H
H
Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8521, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
S
S
Noguchi
R
R
Yoshii
J
J
Ikenaka
Y
Y
Yanase
K
K
Namisaki
T
T
Kitade
M
M
Uemura
M
M
Masaki
T
T
Fukui
H
H
D042702:Angiopoietin-2 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D005822:Genetic Vectors; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*
D042702:Angiopoietin-2; D042461:Vascular Endothelial Growth Factor A; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9