Suppression of renal cell carcinoma growth in vivo by forced expression of vascular endothelial growth inhibitor

Abstract

Vascular endothelial growth inhibitor (VEGI) has been associated with tumor-related vasculature in certain malignancies. However, its implication in renal cell carcinoma (RCC), an angiogenesis-dependent tumor, remains unknown. In the present study, we investigated the role played by VEGI in RCC. The expression of VEGI was examined in human renal tissue and RCC cell lines using immunohistochemical staining and RT-PCR, respectively. The biological impact of modifying the expression of VEGI in RCC cells was evaluated using in vitro and in vivo models. We show that VEGI mRNA is expressed in a wide variety of human RCC cell lines, all of normal renal and most of RCC tissue specimens. VEGI protein expression was observed in normal renal tubular epithelial cells, but was decreased or absent in RCC specimens, particularly in tumors with high grade. Moreover, forced expression of VEGI led to an inhibition of vascular endothelial tube formation, decrease in the motility and adhesion of RCC cells in vitro. Interestingly, forced expression of VEGI had no bearing on growth, apoptosis and invasive capacity of RCC cells. However, tumor growth was reduced in xenograft models. Immunohistochemical staining showed that microvessel density decreased in VEGI forced expression xenograft tumor samples. Taken together, our findings showed that the expression of VEGI is decreased in RCC, particularly in tumors with higher grade. Together with its inhibitory effect on cellular motility, adhesion, vascular endothelial tube formation and tumor growth in vivo, this suggests that VEGI functions mainly through inhibition of angiogenesis and is a negative regulator of aggressiveness during the development and progression of RCC.