Modelling the molecular circuitry of cancer

Abstract

The process of malignant transformation occurs in discrete histopathological steps, many of which correlate with specific genetic alterations. Several lines of evidence implicate a limited number of molecular pathways, the disruption of which contributes to most, if not all, cancers. Rodent and human experimental models of cancer have contributed to our understanding of specific cancer-associated mutations. Although these cancer models share many essential components, several important signalling pathways seem to function differently in human and rodent models of transformation. Immortalization is an essential prerequisite for the formation of a tumour cell. Human cells must circumvent two barriers — replicative senescence and cellular crisis — that limit cell lifespan to achieve immortalization. These barriers are regulated by telomere shortening and by the RB and p53 tumour-suppressor pathways. Ablation of the ARF–p53 pathway suffices to immortalize many mouse cells. Telomere shortening does not seem to limit the lifespan of cells that are derived from inbred mice. In parallel with these differences in immortalization, pairs of introduced oncogenes will transform mouse cells, whereas the transformation of human cells requires additional introduced genes. Identifying and characterizing these species-specific differences will allow the construction of human and rodent models of cancer that increasingly phenocopy human cancer. Such models will revolutionize the screening and testing of candidate chemical and biological anticancer therapies.