Cancer and Evolution

Abstract

Cancer mostly is a disease of old age. Evolutionary pressures have pushed the somatic "error rate", especially the mutation rate, down to a level where for most organisms cancer is no longer of any selective significance. This appears to be a by-product of the selection that gives rise to senescence, following the arguments of Medawar, Holliday, and Kirkwood. The development of a cancer is discussed from an evolutionary viewpoint, emphasising the role of selection versus mutation and the fact that each cancer is an independent evolutionary process. The nature of the selective advantages associated with the somatic genetic changes during a cancer's evolution can sometimes be inferred by reference to the known types of mutations found in cancers. Examples are given using colorectal cancer as a model. The major selective forces involve the balance between selection for increased growth rate and against apoptosis. There are strong arguments against the much discussed role of genomic instability as a requirement for cancer. Current evidence suggests that instability is a byproduct of selection against apoptosis. There is an important contrast between germ line and somatic changes, the former being the basis for inherited susceptibilities to cancer, while the latter are the fundamental changes that turn a normal cell into a cancer cell. Tissue stem cells, as in the colonic crypt, provide the source, through division and differentiation, of the differentiated cells in a crypt. Mathematical models can provide an explanation for how the balance in a crypt between stem cells, intermediate proliferating cells, and non-proliferating differentiated cells is maintained. Perturbations of the renewal parameters in the model can explain the evolution of benign tumors, namely polyps or adenomas, and the eventually exponential growth of cells resulting in a fully developed carcinoma. It seems probable that the origin of most carcinomas is in the intermediate proliferating cells, and that these are therefore the likely source of cancer stem cells.