The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo

Abstract

Vascular endothelial growth factor (VEGF) is known to occur as at least six differentially spliced variants, giving rise to mature isoforms containing 121, 145, 165, 183, 189 and 206 amino acids. However, little is yet known concerning the in vivo activities of this differential splicing. Stably transfected MCF-7 breast carcinoma cells were constructed that secreted comparable amounts of the 121, 165 or 189 isoforms. Rabbit corneal angiogenesis assays showed the VEGF121 transfectant to have much greater angiogenic activity than the 165 or 189 expressing MCF-7 cells. While the VEGF121-expressing MCF-7 cells were reproducibly more tumorigenic than the control transfectants, this was not the case with the VEGF165- or VEGF189-expressing cells. More surprising was the observation that VEGF189 located to the nucleus, consistent with the presence of a highly conserved nuclear localization sequence in exon 6a that is expressed in VEGF189 but not 121 or 165. It was concluded that the VEGF121 isoform is both more angiogenic and tumorigenic than are the 165 and 189 isoforms. This is probably due to the ability of the 121 isoform, unlike the 165 and 189 isoforms, to freely diffuse from the cells producing it.