Growth of new blood vessels (angiogenesis), required for all tumor growth, is stimulated by the expression of vascular endothelial growth factor (VEGF). VEGF is up-regulated in all known solid tumors but also in atherosclerosis, diabetic retinopathy, arthritis, and many other conditions. Conventional VEGF isoforms have been universally described as proangiogenic cytokines. Here, we show that an endogenous splice variant, VEGF 165 b, is expressed as protein in normal cells and tissues and is circulating in human plasma. We also present evidence for a sister family of presumably inhibitory splice variants. Moreover, these isoforms are down-regulated in prostate cancer. We also show that VEGF 165 b binds VEGF receptor 2 with the same affinity as VEGF 165

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 xxx b, where xxx is the amino acid number. The most studied isoforms, VEGF 165 and VEGF 165 b have been shown to be present in tumour and normal tissues respectively. VEGF 165 b 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 VEGF 165 b by tumour cells inhibits the growth of prostate carcinoma, Ewing's sarcoma and renal cell carcinoma in xenografted mouse tumour models. Moreover, VEGF 165 b overexpression inhibited tumour cell-mediated migration and proliferation of endothelial cells. These data show that overexpression of VEGF 165 b can inhibit growth of multiple tumour types in vivo indicating that VEGF 165 b has potential as an anti-angiogenic, anti-tumour strategy in a number of different tumour types, either by control of VEGF 165 b expression by regulation of splicing, overexpression of VEGF 165 b, or therapeutic delivery of VEGF 165 b to tumours.