A University of Colorado Cancer Center presentation at the American Association for Cancer Research Annual Meeting 2017 offers evidence that increased risk for secondary cancers after treatment is due not only to genetic changes caused by treatment but to changes in the tissue landscape that allow cells with cancer–causing mutations to out–compete healthy cells.

The conclusion comes from a long line of research led by James DeGregori, PhD, deputy director of the CU Cancer Center, showing that forces influencing how natural selection acts on heterogeneous populations of cells may be as or more important than new oncogenic events in causing cancer.

Here is a nuanced point: the cells of secondary cancers, especially acute myeloid leukemia (AML), have high rates of p53 mutations. It seems as if this fact supports the traditional model of oncogenesis – perhaps radiation treatment for a first cancer caused these p53 mutations, which then cause secondary AML? However, other studies show that these p53 mutations in fact existed in these cells before treatment. If treatment didn’t cause p53 mutation, why then do p53–mutated cells blossom after treatment?

The DeGregori lab has modeled this process in blood stem cells. When a population of healthy stem cells experiences radiation, one of two things happens: either the cells’ DNA is so damaged that the safety switch of p53 is activated and the cells are killed, or short of that, the stem cells adjust their likelihood of self–renewal so that fewer stem cells make new stem cells and more stem cells make differentiated tissue cells. DeGregori calls this “programmed mediocrity” and it makes sense, allowing the population to “weed out damaged stem cells from their mix without overreacting,” DeGregori says.

Think about it this way: As stem cells divide and die away, the 50/50 chance that a stem cell will make another stem cell or a differentiated tissue cell means that the population can make tissue while keeping the number of stem cells constant. Programmed mediocrity adjusts the odds. Now with, say, only a 40/60 chance of making a stem cell, the population of lightly damaged stem cells will eventually fade away.

When radiation exposure is limited to a few stem cells in a large population, this mechanism built by evolution works well, allowing remaining healthy stem cells to continue out–competing DNA–damaged cells in the tissue for which they are optimized. Maybe a few cells with p53 mutations exist, but they are like Galapagos sparrows whose beaks are the wrong size for the island’s seeds – they are outcompeted by the “sparrows” of healthy cells that are a better fit for the environment.

In this scenario of whole–body radiation, stem cells continue to act according to the instructions of nature. High exposure activates p53, killing cells, and lower exposure results in programmed mediocrity and a slow decline in the population of damaged stem cells. That is, unless p53 is broken. In that case, high exposure wipes out cells with functional p53 while sparing more of those with altered p53. Or “at the same time, modest whole–body radiation selects for other oncogenic mutations that prevent programmed mediocrity,” DeGregori says. If stem cells with oncogenic changes retain a 50/50 chance of producing stem–cell offspring, while healthy cells undergo programmed mediocrity resulting in only a 40/60 chance of producing stem–cell offspring, the pre–cancerous population will eventually out–compete the healthy population. The DeGregori lab has shown that radiation–induced programmed mediocrity leads to selection for stem cells with genes commonly mutated in acute myeloid leukemias, and these mutations lead to greater stem cell self–renewal.