Photocarcinogenesis and Susceptibility to UV Radiation in the v-Ha-ras Transgenic Tg.AC Mouse

Abstract

The v-Ha-ras transgenic Tg.AC mouse line has proven to be a useful model for the study of chemical carcinogenic potential. We undertook experiments designed to study the effect of the physical carcinogen, UV radiation, on tumorigenesis in this mouse strain. Following a total of three exposures on alternating days to a radiation source covering a cumulative UVR exposure range of 2.6-42.6 kJ per m2, squamous papillomas developed by 4 wk after initial exposure in a dose-dependent manner. Malignancies developed within 18-30 wk following the initial UVR exposure and were all diagnosed as squamous cell carcinoma or spindle cell tumors. In contrast to other mouse stains used in photocarcinogenesis studies, few p53 mutations were found in Tg.AC malignancies upon polymerase chain reaction-single stranded conformational polymorphism analysis of exons 4-8 followed by sequencing of suspicious bands; however, all tumors analyzed by in situ hybridization expressed the v-Ha-ras transgene. Immunohistochemical analysis of UVR-exposed skin taken 24 h after the last of three exposures (13.1 kJ per m2 total UVR) showed expression of p53 in hair follicles and in interfollicular epidermis, which indicates that the gene was functional. Thus, although there are some differences between the Tg.AC and other mouse models, these results suggest that the Tg.AC mouse may be a useful model for the study of acute exposure photocarcinogenesis.

12-O-Tetradecanoylphorbol-13-acetate and UV Radiation-induced Nucleoside Diphosphate Protein Kinase B Mediates Neoplastic Transformation of Epidermal Cells

“…TPA-induced papillomas and malignant tumors (spindle cell tumors and squamous cell carcinomas) were identified, removed, and characterized as described previously (6). Tg⅐AC mice were irradiated with combination of 30 -40% UVA and 60 -70% UVB, as described previously (5). After three exposures to UVA/UVB with 8.67 kJ/m 2 per exposure, total cumulative dose of 26 kJ/m 2 , skin tissues (designated as UV1-UV4) were collected 24 h after the last exposure.…”

Chemoprevention of UV Light-Induced Skin Tumorigenesis by Inhibition of the Epidermal Growth Factor Receptor

“…Both practical and scientific considerations led to the selection of v-ras Ha transgenic Tg.AC mice for this experiment. This genetically initiated mouse model rapidly develops skin tumors in response to both mutagenic and nonmutagenic human carcinogens (15)(16)(17). The use of Tg.AC mice, with their uniform initiating mutation and rapid response to skin carcinogens, allows for an examination of the influence of EGFR activation in the promotion process independent of any initiating effects.…”

Biological, cellular, and molecular characteristics of an inducible transgenic skin tumor model: a review

“…Tg.AC mice also develop papillomas in response to fullthickness wounding (Leder et al, 1990;Hansen and Tennant, 1994a;Cannon et al, 1997). UVA/B radiation (Trempus et al, 1998a;Battalora et al, 2001) and to a lesser extent, UVA alone (Chignell et al, 2003b) can generate a tumorigenic response in Tg.AC, an effect that can be diminished by pretreatment with an inhibitor of the epidermal growth factor receptor (EGFR) (ElAbersari et al, 2005). Other wavelengths of radiation have been found to be tumor suppressive (Ohara et al, 2003).…”