The hierarchical model of stem cell genesis explains the man mouse paradox, Peto's paradox, the red cell paradox and Wright's enigma

Abstract

The central dogma of carcinogenesis is that deleterious mutations accumulate in regularly cycling stem cells and eventually one of the cells will acquire a specific set of mutations which leads to uncontrolled cell proliferation. Each mutation is rare and the specific set is extremely rare so that even though there are millions of stem cells in a small area of mucosa the specific set of mutations to initiate the process of malignancy will only arise in one stem cell at most; hence neoplasia is clonal. But this model predicts that men, who are 1000 times larger than mice and live 30 times as long, should have a vastly increased risk of cancer compared with mice, but they don't (man-mouse paradox). The model also predicts that the prevalence of cancer in men should rise as power function of age and mutagen dose, the former is correct but not the latter (Peto's paradox). Furthermore there are more mitotic divisions in red cell precursors than in all other stem cells combined and yet erythroleukaemia is rare (red cell paradox). The central dogma is also challenged by Wright's enigma; the observation that some gastro-intestinal neoplasms are polyclonal in origin. The problem with the central dogma is the concept of a regularly cycling stem cell. In fact it is possible to produce all the cells that arise in a human lifetime with fewer than 60 rounds of DNA replication separating the zygote from mature differentiated cells in extreme old age. This hierarchical model of stem cell genesis leads to a very low prevalence of cancer, unless the orderly progression of the hierarchy is disturbed by inflammation, ulceration or trauma. This model explains the paradoxes and Wright's enigma. It is suggested that the number of cell divisions that separate the zygote from stem cells is a key variable in carcinogenesis.