Involvement of the vascular endothelial growth factor receptor-1 in murine hepatocellular carcinoma development |
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Authors: | Yoshiji Hitoshi Kuriyama Shigeki Yoshii Junichi Ikenaka Yasuhide Noguchi Ryuichi Yanase Koji Namisaki Tadashi Kitade Mitsuteru Yamazaki Masaharu Tsujinoue Hirohisa Masaki Tsutomu Fukui Hiroshi |
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Institution: | Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, 634-8522 Nara, Japan. yoshijih@naramed-u.ac.jp |
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Abstract: | BACKGROUND/AIMS: 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. |
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