COMPARATIVE EXPRESSION OF NOVEL VASCULAR ENDOTHELIAL GROWTH-FACTOR VASCULAR-PERMEABILITY FACTOR TRANSCRIPTS IN SKIN, PAPILLOMAS, AND CARCINOMAS OF V-HA-RAS TG.AC TRANSGENIC MICE AND FVB N MICE/

One of the most frequently detected changes in human solid tumors is t he mutation of the ras oncogene, which has been associated with produc tion of angiogenic growth factors such as vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). Using the v-Ha-ras Tg. AC transgenic mice and the background FVB/N strain of inbred mice, the pattern of expression of specific VEGF/VPF transcripts was characteri zed in major organs and in skin, papillomas, and carcinomas during mul ti-stage skin carcinogenesis. Three VEGF/VPF transcripts were found to be constitutively expressed in skin as well as the major organs in bo th mouse strains, which corresponded in size and sequence to previousl y reported murine VEGF(120) with a bp size of 331, VEGF(164) with a bp size of 333, and VEGF(188) with a bp size of 407. A previously unrepo rted fourth murine transcript was also detected in skin and major tiss ues from both mouse strains which corresponded to rat VEGF(144), with a bp size of 404. In addition, a unique 425 bp VEGF transcript which c orresponded to human VEGF(206) was present in highly vascularized tiss ues including heart, lung, liver, kidney, brain, as well in papillomas and carcinomas isolated from v-Ha-ras Tg.AC mice. In contrast, VEGF(2 05) was present only in carcinomas derived from FVB/N mice. An antibod y generated from a peptide sequence designed to detect each of the fiv e VEGF/VPF peptides defined by RT-PCR analysis confirmed the existence of these five peptides and confirmed that the murine VEGF(205) peptid e was selectively expressed in papillomas and carcinomas derived from v-Ha-ras Tg.AC mice. These results demonstrate that there is significa nt alternative splicing of the murine VEGF/VPF gene during multi-stage carcinogenesis, which results in four commonly expressed VEGF transcr ipts. In addition, these studies identified a fifth VEGF transcript an d peptide at the later stages of tumor promotion and in progression wh ich appears to be linked to the presence of v-Ha-ras. (C) 1998 Academi c Press.