Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice.
It has been shown that angiogenesis plays an important role not only in tumor growth, but also in early carcinogenesis. The expression of a potent angiogenic factor, vascular endothelial growth factor (VEGF), increased during the early stage of carcinogenesis. In this study, the effects of the neutralizing monoclonal antibodies R1 mAb and R2 mAb of the VEGF receptors Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), respectively, on murine hepatocarcinogenesis induced by diethylnitrosamine (DEN) were examined. The effects of R1 mAb and R2 mAb on spontaneous lung metastasis from hepatocellular carcinoma (HCC) were also investigated. VEGF expression and neovascularization in the tumor increased stepwise during hepatocarcinogenesis. Treatment with both R1 mAb and R2 mAb markedly inhibited the development of HCC and adenoma in the liver. The inhibitory effect of R2 mAb was more potent than that of R1 mAb, and the combination treatment with both mAbs almost completely attenuated hepatocarcinogenesis. Both R1 mAb and R2 mAb treatment significantly suppressed the development of angiogenesis in HCC. The suppressive effects against angiogenesis R1 mAb and R2 mAb were similar in magnitude to their inhibitory effects against hepatocarcinogenesis. Furthermore, spontaneous lung metastasis from HCC was also significantly suppressed by R1 mAb and R2 mAb treatment. In conclusion, these results suggest that VEGF and receptor interaction plays an important role in hepatocarcinogenesis and in spontaneous lung metastasis from HCC.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Nara, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
Shigeki
S
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Noguchi
Ryuichi
R
Hicklin
Daniel J
DJ
Wu
Yan
Y
Yanase
Koji
K
Namisaki
Tadashi
T
Kitade
Mitsuteru
M
Yamazaki
Masaharu
M
Tsujinoue
Hirohisa
H
Masaki
Tsutomu
T
Fukui
Hiroshi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology
D000911:Antibodies, Monoclonal; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2