This is the mutation accumulation theory of oncogenesis: “Cancers are caused by mutations that may be inherited, induced by environmental factors, or result from DNA replication error,” write John Hopkins University biostatisticians Tomasetti, Li and Vogelstein in the March 24, 2017 issue of the journal Science.

But there is a parallel thread through these causes of cancer that reaches a much different endpoint. This is the thread of the microenvironment – the ecosystem of the body’s tissues. Age and exposures like smoking and UV radiation damage the body’s tissues. Writing in the journal Cancer Research, James DeGregori, PhD, deputy director of the University of Colorado Cancer Center offers evidence that it is forces of evolution driven by natural selection acting in the ecosystem of the body that, in the presence of tissue damage, allow cells with dangerous mutations to thrive. This evolutionary theory of cancer points out that cells containing dangerous mutations exist all the time, but are commonly out–competed by healthy cells that are optimized to live in healthy tissue. It is only when the tissue microenvironment is degraded (by smoking, sun, chemical exposure, age, etc.) that cells with these mutations find themselves most fit and suddenly able to out–compete healthy cells and so establish themselves in the landscape of the body. Mutations are still required for cancers, but changes in our tissues as we age or engage in activities like smoking are the primary determinants of “who gets cancer, how cancer risk relates to known causes, which tissues it occurs in, and when the cancers develop in life,” DeGregori writes.

A piece of DeGregori’s argument rests in the fact that cancer rates do not match mutation rates. He points out that humans will hold about half their lifetime complement of mutations by young adulthood (at which point cells relax the frantic pace of replication used to build the adult body). However, the likelihood of developing cancer does not match this rate of mutation – despite having half of the lifespan’s mutations, young adults have much less than half of the lifespan’s cancer risk.

DeGregori also shows that along with mismatching the number of mutations in cells, cancer risk also mismatches the number of cells in tissue. According to Tomasetti and colleagues, more cells and more replication should lead to more chance mutations and eventually to more cancer. However, across species this is not true – a blue whale has about 7 million times more cells than a mouse and yet the whale has no more cancer risk across its lifespan. Researchers refer to this as Peto’s Paradox.

DeGregori points out that the mismatch between mutational burden and cancer risk is vividly demonstrated by mice with a genetic malfunction that leads to dramatically increased mutation rate (an error in a specific DNA proofreading function). In these mice, many more mutations lead to no increase in cancer rates. It is not the presence of mutations nor the rate at which mutations occur that drive the timing and incidence of cancer.

Work by DeGregori and others has also shown that cancer–causing mutations often make cells less fit. Cells in our tissues are close to “just right” for healthy young tissues; cancer–causing mutations can disrupt this adaptation, leading to cells that are no longer optimized to their surroundings and eventually leading to elimination of mutant cells from the tissue. That is unless disruption of the tissue in old age or following carcinogenic exposures adjusts the surroundings in ways that make these same mutations advantageous.

In all, “Lifetime mutation accumulation in stem cells cannot explain varying cancer predisposition across tissues and species. Instead, we need to consider how aging or carcinogens change tissue microenvironments to increase selection for particular oncogenic mutations,” DeGregori writes.