Send to

Choose Destination
See comment in PubMed Commons below
Hepatology. 1999 Nov;30(5):1179-86.

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

Author information

Third Department of Internal Medicine, Nara Medical University, Nara, Japan.


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.

[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Wiley
    Loading ...
    Support Center