Multistage carcinogenesis

Abstract

The major stages of chemical carcinogenesis have been deduced over the past ~50 years, primarily from animal model studies (and particularly from studies using the mouse skin model); these stages are termed initiation, promotion, and progression. Tumor initiation begins when DNA in a cell or population of target cells is damaged by exposure to exogenous or endogenous carcinogens leading to mutations in critical target genes. The responsiveness of initiated cells to their microenvironment gives them a growth advantage relative to normal cells under certain conditions. In the classic two-stage chemical carcinogenesis system in the mouse skin, a low dose of a carcinogen such as 7,12-dimethylbenz(a)anthracene induces a mutation in Hras1 that does not give rise to tumors over the lifespan of the mouse unless a tumor promoter, such as TPA, is repeatedly applied. The tumor promotion stage is characterized by selective clonal expansion of the initiated cells, a result of the altered expression of genes whose products are associated with hyperproliferation, tissue remodeling, and inflammation. During tumor progression, preneoplastic cells undergo malignant transformation through a process of selection that is facilitated by progressive genomic instability and altered gene expression. While the processes involved in each stage of experimental chemical carcinogenesis also appear to be involved in human carcinogenesis, the temporal nature of initiation, promotion, and progression events is more complex. In addition, multiple mutational events are involved in the formation of human tumors. Genetic background and nutritional status can dramatically affect susceptibility to a carcinogenic exposure in both experimental animals and humans. An understanding of the multistage nature of carcinogenesis has led to the discovery of mechanismbased inhibitors that target events associated with specific stages. Further study of the cellular, biochemical, and molecular mechanisms associated carcinogenesis induced by chemicals and other types of carcinogens will lead to identification of effective strategies for cancer prevention. © Springer Science+Business Media, LLC 2011.