Involvement of the vascular endothelial growth factor receptor-1 in murine hepatocellular carcinoma development.
OBJECTIVE
The role of the vascular endothelial growth factor receptor-1 (VEGFR-1) in hepatocellular carcinoma (HCC) development has not been elucidated yet. The aim of this study was to examine the role of VEGFR-1 in VEGF-mediated HCC development and angiogenesis as compared to that of VEGFR-2.


METHODS
We examined the effects of VEGFR-1, and VEGFR-2 neutralizing monoclonal antibodies (R-1mAb and R-2mAb, respectively) on VEGF-mediated HCC development both in an allograft and orthotopic models.


RESULTS
In the allograft model, both R-1mAb and R-2mAb significantly attenuated the VEGF-mediated tumor development in a dose dependent manner with associated reduction of angiogenesis in the tumor. The inhibitory effect of R-2mAb was more potent than that of R-1mAb, and the combination treatment with both mAbs almost completely attenuated VEGF-mediated HCC development. Immunohistochemical analysis revealed that apoptosis increased markedly in the tumor. Furthermore, these inhibitory effects with both mAbs were achieved even on established tumors and orthotopic transplantation.


CONCLUSIONS
In addition to VEGFR-2, VEGFR-1 also lies on the signal transduction pathway by which VEGF augments HCC development and angiogenesis not only at the initial stage but also in the established tumor.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, 634-8522 Nara, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
Shigeki
S
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Noguchi
Ryuichi
R
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; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism*; D002455:Cell Division; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000276:immunology / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2