The endogenous anti-angiogenic VEGF isoform, VEGF₁₆₅b inhibits human tumour growth in mice

Vascular endothelial growth factor-A is widely regarded as the principal stimulator of angiogenesis required for tumour growth. VEGF is generated as multiple isoforms of two families, the pro-angiogenic family generated by proximal splice site selection in the terminal exon, termed VEGF_xxx, and the anti-angiogenic family formed by distal splice site selection in the terminal exon, termed VEGF_xxxb, where xxx is the amino acid number. The most studied isoforms, VEGF₁₆₅ and VEGF₁₆₅b have been shown to be present in tumour and normal tissues respectively. VEGF ₁₆₅b has been shown to inhibit VEGF- and hypoxia-induced angiogenesis, and VEGF-induced cell migration and proliferation in vitro. Here we show that overexpression of VEGF₁₆₅b by tumour cells inhibits the growth of prostate carcinoma, Ewing's sarcoma and renal cell carcinoma in xenografted mouse tumour models. Moreover, VEGF₁₆₅b overexpression inhibited tumour cell-mediated migration and proliferation of endothelial cells. These data show that overexpression of VEGF₁₆₅b can inhibit growth of multiple tumour types in vivo indicating that VEGF₁₆₅b has potential as an anti-angiogenic, anti-tumour strategy in a number of different tumour types, either by control of VEGF₁₆₅b expression by regulation of splicing, overexpression of VEGF₁₆₅b, or therapeutic delivery of VEGF₁₆₅b to tumours.