Models of carcinogenesis

The simplest experimental model of carcinogenesis is the three-stage model consisting of initiation, promotion and progression.19 At the initiation stage, a single cell is thought to acquire a mutation and then divide repeatedly so that the mutation is passed on to a clone of daughter cells, thus forming a focal lesion that can survive and grow at the expense of neighbouring cells. During promotion, the normal constraints on proliferation and spatial organisation within the affected tissue are disrupted further, and the appearance of further mutations to proto-oncogenes and tumour suppressor genes leads to a progressive loss of differentiation and orderly growth. The genes involved in this transition to cancer, and the functions they perform, are under intensive investigation and are particularly well characterised in the intestinal epithelium.20

At the progression stage the lesion has made the transition to malignancy and can give rise to secondary tumours at remote sites. Animal models have been used to identify specific carcinogenic substances which can act as mutagens at the intiation stage but do induce malignancy on their own, promoters which cannot initiate tumours but do accelerate tumour development after initiation, and complete carcinogens, which can do both. As we shall see later, this approach has also been used to identify inhibitors of carcinogenesis and to delineate their mode of action. The difficulty with animal models of carcinogenesis is that they usually require the application of large doses of carcinogens and promoters to groups of rodents, so that a high tumour yield is obtained during the course of the experiment. Such techniques are a poor model for induction of human cancers because these are usually caused by very prolonged exposure to a complex array of unknown carcinogenic stimuli over the course of a lifetime. However, there is no doubt that much of the fundamental understanding of tumour biology that has been gained from animal studies applies also to human disease.

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