Chemical carcinogenesis models of cancer: Back to the future

Abstract

Over a century has elapsed since the first demonstration that exposure to chemicals in coal tar can cause cancer in animals. These observations provided an essential causal mechanistic link between environmental chemicals and increased risk of cancer in human populations. Mouse models of chemical carcinogenesis have since led to the concept of multistage tumor development through distinct stages of initiation, promotion, and progression and identified many of the genetic and biological events involved in these processes. Recent breakthroughs in DNA sequencing have now given us tools to dissect complete tumor genome architectures and revealed that chemically induced cancers in the mouse carry a high point mutation load and mutation signatures that reflect the causative agent used for tumor induction. Chemical carcinogenesis models may therefore provide a route to identify the causes of mutation signatures found in human cancers and further inform studies of therapeutic drug resistance and responses to immunotherapy, which are dependent on mutation load and genetic heterogeneity.