Evolutionary principles used to model cancer mutations and discover potential therapeutic targets
Researchers are taking a unique approach to understanding and investigating cancer. Utilizing evolutionary principles and computational modeling, the role of specific genetic mutations in the Darwinian struggle among tumor and normal cells during cancer growth is examined.
Cells become malignant by acquiring genetic mutations that lead to increased survival and reproduction. Many researchers in the past have viewed cancer progression as the result of unlimited accumulation of these genetic mutations.
However, these researchers, with Moffitt Cancer Center in Tampa, Florida, modeled cancer progression on the premise that cancer cells live in an environment that has limited resources, such as space and nutrients. Like all living organisms, cancer cells must obey the laws of evolution, including trade-offs between proliferation and survival.
For example, elephants use their available resources primarily to maximize survival, so they have relatively long lives and few offspring. Rabbits, on the other hand, produce many offspring but survive in the wild for less than 2 years.
Mutations observed in cancer cells are limited to this same evolutionary trade-off. Cells that evolve to form cancers can do so by either increasing longevity or increasing their number. With this in mind, cancer cells can invest available resources to maximize their defenses against attacks from normal tissue or overcome a high rate of mortality through very rapid proliferation, but not both.
The researchers performed computer simulations based on these concepts. They found that the frequency with which any genetic mutation is observed depends on its ability to increase the cell's fitness, its ability to survive, and reproduce. The researchers called this process evolutionary triage. Their work was published in Nature Communications (2014; doi:10.1038/ncomms6499).
“Genes that increase fitness are observed more frequently than those that do not,” explained Robert A. Gatenby, MD, chair of the Department of Diagnostic Imaging and co-director of the Cancer Biology and Evolution Program at Moffitt.
“However, the effect of any mutation on cell fitness can change drastically depending on environmental factors such as blood flow, past genetic mutations, and the properties of competing cells. Currently, cancer biologists divide mutations into drivers, which promote tumor growth and passengers, which have no effect on growth. In the computer simulations, it was clear that many mutations could be drivers in one environment, but passengers in another.”
The investigators were startled to find that some genes were actually never observed to be mutated in cancers. It turned out that mutations in these genes always reduced the tumor cell's ability to survive or reproduce. As a result, even when they occurred, evolutionary triage eliminated them because they were less fit than their competitors.
According to Gatenby, “our computer simulations demonstrate an unexpected result: genes that are never observed to be mutated might actually be the best targets for therapy. This is because up or down regulation of these genes unconditionally reduces cell fitness.”