Animal Models of Chemical Carcinogenesis: Driving Breakthroughs in Cancer Research for 100 Years

Abstract

The identification of carcinogens in the workplace, diet, and environment through chemical carcinogenesis studies in animals has directly contributed to a reduction of cancer burden in the human population. Reduced exposure to these carcinogens through lifestyle changes, government regulation, or change in industry practices has reduced cancer incidence in exposed populations. In addition to providing the first experimental evidence for cancer's relationship to chemical and radiation exposure, animal models of environmentally induced cancer have and will continue to provide important insight into the causes, mechanisms, and conceptual frameworks of cancer. More recently, combining chemical carcinogens with genetically engineered mouse models has emerged as an invaluable approach to study the complex interaction between genotype and environment that contributes to cancer development. In the future, animal models of environmentally induced cancer are likely to provide insight into areas such as the epigenetic basis of cancer, genetic modifiers of cancer susceptibility, the systems biology of cancer, inflammation and cancer, and cancer prevention.

Figure 1. Model of urethane induced lung cancer

A. Following intraperitoneal injection, urethane is metabolized by the p450 system to highly reactive vinyl carbamate epoxide which covalently binds to DNA, and can result in base misincorporation during DNA replication and point mutations. ~80% of urethane induced lung tumors contain Kras^Q61L mutations and additional genetic and epigenetic events that contribute to tumor progression. These additional events include mutation of p53 (Horio et al., 1996), mislocalization of p27 (Kelly-Spratt et al., 2009), altered DNA methylation (Alyaqoub et al., 2007), and loss of p19/Arf expression (S. Bush and C. Kemp, unpublished data). B: Combined urethane with GEM models to reveal genotype x environment interaction. Shown are the mean number of urethane induced lung tumors >1 mm in diameter in 30 week old 129 × C57BL/6J F₁ p27+/+ (wild type) and p27−/− (nullizygous) littermate mice. Mice were either untreated (control) or injected with urethane at 12 days of age (1mg/g body wt). Neither wild type nor p27 nullizygous mice spontaneously developed lung tumors. Urethane treated wild type mice developed an average of 1.5 tumors per mouse while p27−/− mice averaged 11 tumors per mouse. On the right are representative lungs from urethane treated 50 week old mice of the indicated genotype. This reveals that urethane exposure and germline deletion of p27 interact synergistically to accelerate lung tumor development and demonstrates that p27 is a potent barrier to chemically induced cancer.