KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells.

Vascular endothelial growth factor (VEGF), which is one of the most potent angiogenic factors, has been shown to play a pivotal role in tumor angiogenesis, including hepatocellular carcinoma (HCC). The effects of VEGF are mediated mainly through two distinct receptors, flt-1 and KDR/Flk-1. It has been suggested that KDR/Flk-1 plays an important role in tumor development. However, the role of KDR/Flk-1 in HCC has not been examined. We previously reported that VEGF tightly regulated murine HCC development, based on the results of a study using a retroviral tetracycline-regulated (Retro-Tet) gene expression system. This system allows VEGF gene expression to be manipulated in vivo by providing tetracycline in the drinking water. In the present study, we combined the KDR/Flk-1-specific neutralizing monoclonal antibody (KDR/Flk-1mAb) and the Retro-Tet system to elucidate the role of KDR/Flk-1 in VEGF-induced tumor development and angiogenesis in a murine HCC experimental model. In a xenograft study, tumor augmentation induced by VEGF overexpression was almost abolished by means of KDR/Flk-1mAb treatment, with accompanying inhibition of angiogenesis, KDR/Flk-1 autophosphorylation, but not interference of flt-1 activation. This inhibitory effect was achieved even on established tumors and regardless of whether the tumor size was small or large. On the contrary, KDR/Flk-1mAb treatment significantly increased the apoptosis in the tumor. With orthotopic transplantation, KDR/Flk-1mAb also inhibited HCC development in the liver. These results suggest that KDR/Flk-1 is a major regulator of VEGF-mediated HCC development and angiogenesis not only at the initial stage, but also after the tumor has fully developed.

Yoshiji H ，Kuriyama S ，Hicklin DJ ，Huber J ，Yoshii J ，Miyamoto Y ，Kawata M ，Ikenaka Y ，Nakatani T ，Tsujinoue H ，Fukui H ... -  《HEPATOLOGY》

Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma.

Yoshiji H ，Kuriyama S ，Yoshii J ，Ikenaka Y ，Noguchi R ，Hicklin DJ ，Huber J ，Nakatani T ，Tsujinoue H ，Yanase K ，Imazu H ，Fukui H ... -  《HEPATOLOGY》

Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis.

Yoshiji H ，Kuriyama S ，Ways DK ，Yoshii J ，Miyamoto Y ，Kawata M ，Ikenaka Y ，Tsujinoue H ，Nakatani T ，Shibuya M ，Fukui H ... -  《CANCER RESEARCH》

The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model.

Yoshiji H ，Kuriyama S ，Hicklin DJ ，Huber J ，Yoshii J ，Ikenaka Y ，Noguchi R ，Nakatani T ，Tsujinoue H ，Fukui H ... -  《HEPATOLOGY》

Different cascades in the signaling pathway of two vascular endothelial growth factor (VEGF) receptors for the VEGF-mediated murine hepatocellular carcinoma development.

Yoshiji H ，Noguchi R ，Kuriyama S ，Yoshii J ，Ikenaka Y ，Yanase K ，Namisaki T ，Kitade M ，Yamazaki M ，Uemura M ，Fukui H ... -  《ONCOLOGY REPORTS》