Melanoma models for chemoprevention and ultraviolet radiation susceptibility

Abstract

Worldwide the incidence rate of melanoma has risen while other cancer trends decrease. Late stages of melanoma carry a severe prognosis and the cancer is one that afflicts young adults relatively frequent. Treatment options are very few and survival rates remain low in metastatic disease. Models for evaluating new treatments, chemoprevention and melanoma progression are needed. The first model system described here involves the use of chemical carcinogenesis to induce melanoma in a transgenic mouse system, the TPras mouse. The analysis of tumors that developed on these mice demonstrates that this model system has genetic alterations that are much like the human disease, namely the loss or alteration of the tumor suppressor p16 protein, increase in Ras protein and altered PKC expression. The in vitro system from the TP-ras mouse is also used to compliment the in vivo studies for the effectiveness of perillyl alcohol (POH) as a chemoprevention agent of melanoma in the TPras mice. The mechanisms of POH activity are a decrease in Ras protein levels as well as ras downstream effectors, Akt and MAPK. POH causes only a slight increase in apoptosis while it greatly diminishes the production of UV induced reactive oxygen species (ROS). The activity of POH in vitro suggests a mechanism for the chemopreventive effect seen with POH in the TPras mice. The second model described herein mimics the human risk factor for melanoma of light pigmentation. An increase in UV induced tumors is demonstrated in the Avy mice, which are a lighter pigmented mouse than the TPras mice. Thymine dimer production in vitro demonstrated only a mild sunscreen effect of the darker pigmented melanocytes. However the evaluation of ROS production induced by UV indicated that the melanocytes from the lighter pigmented mouse were able to produce much greater levels of ROS both from UVB and UVA induction. These studies suggest that oxidative damage may contribute to melanoma susceptibility in lighter pigmented individuals. In summary, this work has validated the Avy and TPras mouse models for studying risk factors and testing chemoprevention agents, respectively, in melanoma.