Different cascades in the signaling pathway of two vascular endothelial growth factor (VEGF) receptors for the VEGF-mediated murine hepatocellular carcinoma development.
It has been shown that the interaction between the potent angiogenic factor; the vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2), plays a pivotal role in tumor development, including hepatocellular carcinoma (HCC). However, the properties of the respective VEGF receptor in the signaling transduction pathway of VEGF-mediated effects in HCC have not been elucidated yet. The aim of this study was to examine the respective signaling pathway of two VEGFRs in the VEGF-mediated murine HCC development and angiogenesis. We examined the signaling cascades of VEGFR-1 and VEGFR-2 in the VEGF-mediated HCC development in combination with a retroviral tetracycline (tet)-regulated (Retro-Tet) gene expression system, which can manipulate the gene expression in vivo by providing tet in the drinking water, as well as VEGFR-1 and VEGFR-2 specific neutralizing monoclonal antibodies (R-1mAb and R-2mAb, respectively). Both R-1mAb and R-2mAb significantly suppressed the VEGF-mediated tumor growth associated with reduction of the tumoral neovascularization, and the combination treatment with both mAbs almost completely attenuated the tumor development and angiogenesis. The protein kinase-C (PKC) and MEK1/2 activities in the tumor were markedly attenuated by treatment with R-2mAb, whereas R-1mAb did not alter these activities. These results suggested that both VEGFR-1 and VEGFR-2 play important roles, and lie in the different signaling cascades by which VEGF augments HCC development and angiogenesis.
Yoshiji
Hitoshi
H
The Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
Noguchi
Ryuichi
R
Kuriyama
Shigeki
S
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Yanase
Koji
K
Namisaki
Tadashi
T
Kitade
Mitsuteru
M
Yamazaki
Masaharu
M
Uemura
Masahito
M
Fukui
Hiroshi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D002455:Cell Division; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000473:pathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000187:drug effects / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000235:genetics*
D000911:Antibodies, Monoclonal; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2