| The murine multistage skin carcinogenesis model has been used to characterize the development and progression of human squamous cell carcinogenesis. In this model, mice are initiated with a single topical dose of the polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) which induces stable and heritable mutations in the cellular Harvey ras protooncogene. Cells which contain these mutations are induced to selectively clonally expand into benign papillomas by the topical application of the phorbol ester tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA). These lesions expand to 1--2 mm3, at which point they must begin to recruit a new blood supply, a process called angiogenesis, in order to remain viable. There are several pro-angiogenic factors including basic fibroblast growth factor (bFGF), placenta derived growth factor (PIGF), the angiopoeitins Ang-1 and Ang-2, and the most potent prot-angiogenic factor vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). VEGF/VPF is a single gene produces 3 alternative splice variants in rodents including VEGF 120, VEGF164, and VEGF188. The results of the present studies demonstrate the existence of 2 additional mouse VEGF/VPF splice variants, VEGF144 which is 87% homologous to human VEGF145 , and VEGF205. While VEGF144 was substantially elevated in both papillomas and carcinomas, VEGF205 was present only in highly vascularized organs and in papillomas isolated from v-Ha- ras Tg.AC transgenic mice and in carcinomas. VEGF144 was found to be the most highly upregulated angiogenic factor throughout papilloma development in this model compared to the other VEGF transcripts, bFGF, PIGF, Ang-1 or Ang-2. In addition, expression of VEGF144 was associated with increased susceptibility of mouse strains to chemical carcinogenesis in the skin. Taken together, these studies indicate that alternative splice variants of VEGF/VPF A, specifically VEGF144 and VEGF205 and their associated receptors on the vascular endothelium, may be potentially useful for the development of strategies for the treatment and prevention of squamous cell carcinoma in the skin. |
