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

✍ Scribed by Hitoshi Yoshiji; Shigeki Kuriyama; Daniel J. Hicklin; James Huber; Junichi Yoshii; Yoji Miyamoto; Mitsuhiro Kawata; Yasuhide Ikenaka; Toshiya Nakatani; Hirohisa Tsujinoue; Hiroshi Fukui

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 375 KB
• Volume: 30
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510300509

✦ Synopsis

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. (HEPATOLOGY 1999;30:1179-1186.