Cancer prevention approaches disease from wrong angle, new evidence says

New evidence suggests that genetic mutations in the cells of the human body may not be the sole cause of cancer. In a July 31 article in the journal, Cancer,  James DeGregori, PhD, deputy director of the University of Colorado Cancer Center, writes 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.

Historically, smoking, sun, and chemical exposure, along with genetic predispositions and old age, were known to increase an individual's risk of developing cancer. One thread connecting these risks is genetic mutations in human cells. For example, smoking and UV exposure increase the rate of damaged DNA, which can replicate and pick up a mutation that causes cancer. 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, according to John Hopkins University biostatisticians in the March 24 issue of the journal, Science.

However, there is a parallel thread through these causes of cancer that reaches a much different endpoint—the microenvironment, or the ecosystem of the body's tissues. Age and exposures like smoking and UV radiation damage the body's tissues. DeGregori's 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 that cells with mutations find themselves most fit and suddenly able to out-compete healthy cells, and can establish themselves in the landscape of the body, says DeGregori.

Mutations are still required for cancers, according to DeGregori, but changes in tissues from engaging in activities like smoking are the primary determinants of who gets cancer, how cancer risk relates to known causes, which tissues cancer occurs in, and when the cancer develops.

One way to visualize DeGregori's theory is with the meteor that ended the reign of the dinosaurs. The meteor's dramatic restructuring of the Earth's ecosystems rendered dinosaurs less fit and also stimulated the evolution of many new species, including a variety of mammalian species. Environmental change promotes speciation. A similar process in our tissues can lead to what is essentially a new cellular species, cancer.

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 John Hopkins University biostatisticians, 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.

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, says DeGregori. 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, whereas 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.

One implication is that research into cancer prevention has been approaching the disease from the wrong angle. If the field believes that mutations are the major factor causing cancer, then preventing cancer depends on preventing mutations. However, if the field looks through DeGregori's lens of evolutionary competition between cancer cells and healthy cells, dependent on their relative adaptation to microenvironments, then preventing cancer depends on maintaining a tissue ecosystem that favors healthy cells.

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