Why is cancer so common a disease in people yet so rare at a cellular level?

Cancers are common diseases in people and yet, on a cellular level, are quite rare. The vast majority of both sporadic, spontaneous cancers and inherited germline cancers arise in single foci from singly transformed cells despite the fact that, in the former, carcinogenic factors bathe fields of millions of potential target cells and, in the latter, the predisposing germline mutations are present in every cell of a given organ and, in fact, every cell of the body. Although the multi-hit theory of carcinogenesis has been invoked to explain such things as cancer latency, which is the period between cancer initiation and emergence and the cancer-aging relationship where an accumulation of "hits" over a period of time are necessary for cancer emergence, the multi-hit theory falls short in explaining the rareness of transformation at a cellular level. This is so because many cancers are not due to multiple hits, and even for those that are, it would be expected that many cells would be exposed to those factors inducing the hits. Although the tumor stem/progenitor cell compartmental theory of tumorigenesis characterizes a tumor compartment that is capable of self-renewal and multipotency, accounting for cancer relapses and recurrences, this compartmental theory alone cannot account for the rareness of initial transformation at a cellular level as the cancer stem/progenitor cell compartment is already transformed and considerable in size. This study advances a different and novel hypothesis that oncogenesis is regulated and ultimately determined by a cell of origin's critical state of differentiation. Before and after this critical state of differentiation has been reached, target cells cannot transform and give rise to cancer even when they receive the necessary carcinogenic insults or have the requisite transforming tumor suppressor genes or oncogenes. As support for this hypothesis, the study cites preliminary evidence using oncogene-containing transgenic mice that develop mammary carcinomas, to derive tail vein fibroblasts converted to iPSCs which, when left undifferentiated, and injected into the cleared fat pads of non-transgenic background mice give rise to mammary gland ontogeny and mammary gland carcinogenesis. However, when first differentiated in vitro into multiply different non-mammary lineages prior to injection, they fail to do so. The hypothesis has widespread implications for chemopreventive strategies.