Abstract

Mouse cancer models have helped us to develop and understand the concept of multistage tumour development from single initiated cells to metastasis. We know that advanced tumours both in mouse and human are heterogeneous at the genetic level, comprising many subclones that contribute to development of drug resistance and poor patient outcomes. A combination of genetic and chemical models of carcinogenesis in the mouse is uniquely able to provide insights into the clonal evolution of cancers at the cellular level, by labelling individual cells, either in the whole tissue or in subpopulations of stem cells, and following their fate changes at different stages of tumorigenesis. We have used the DMBA /TPA model of squamous carcinoma development in the skin of the K5CreER-Confetti mouse together with stage-specific lineage tracing to analyze the clonality of initiation, development of benign tumours, progression to carcinomas and further to metastasis. Additional models in which specific stem cell populations can be traced during normal development and tumor formation have enabled us to investigate the relationship between normal and cancer stem cells, the impact of “cell of origin” on tumour phenotype, and the probability of malignant progression from “high risk” benign tumours.