Helping cells win the evolutionary war

Science Article

Computational biologist Maley, Reid collaborate to evaluate competitive forces inside esophageal tumors

This composite image shows the graphic interface for a mathematical model by Dr. Carlo Maley. The model simulates the dynamics of progression in a Barrett's esophagus tumor, including cells with mutations that spread over a tumor. Each frame is a slice of time. Image courtesy of Carlo Maley and Keith Wiley

Darwin may not have been thinking about cancer when he developed his theory on evolution. But his insight turns out to explain a lot about how malignant cells arise and wreak havoc on normal tissue.

Hutch scientists hope that by using an evolutionary perspective to study cancer - a disease in which abnormal cells multiply at the expense of healthy cells - they will learn not only something about how cancer progresses but also how and when to intervene to halt the disease process.

Dr. Brian Reid and computational biologist Dr. Carlo Maley are exploring the competitive forces at work inside esophageal tumors with the ultimate goal of helping the healthy cells win the evolutionary war.

"We see cancer as an evolutionary process, with certain cells gaining a selective advantage," said Reid, head of the Seattle Barrett's Esophagus Program and an investigator in the Public Health Sciences and Human Biology divisions.

Mathematical model

Maley has developed a mathematical model that indicates that if benign cells could be stimulated to grow, they might out-compete their malignant neighbors.

After the model is refined, the next goal will be to identify systems in which "benign booster" drugs could be identified and tested. This could hold promise for future cancer treatment.

"We've approached an important new frontier to develop the tools to understand the disease process," Reid said. "That will ultimately tell us where to intervene."

Schoolbook examples of evolution usually focus on societies of organisms competing for food and resources, like Darwin's well-studied finches. Animals with certain physical characteristics, such as longer beaks or better eyesight, might have an easier time finding food, gaining a survival and reproductive advantage over their neighbors.

Human or animal bodies, consisting of millions of cells that must interact cooperatively to produce offspring, also can be considered as societies. But if mutations arise in some cells, reducing or eliminating their cooperative nature, a tumor may grow in which cells compete for resources. The breakdown of the cooperation between cells in a body, and the resulting cancer, is usually fatal not only for some of the competing cells in the tumor, but also for the body as a whole.

Three requirements

Maley said tumors can be described by Darwin's three requirements for natural selection, a process by which individuals in a population with certain characteristics gain a selective advantage, surviving and reproducing more efficiently than others lacking those traits.

"Within a tumor, there is variation in the population, since there can be many different abnormal cell types," he said.

"Second, the variation has to be heritable. Because much of the variation in tumor cells is due to changes in the DNA, this condition is met.

"Third, the variation has to affect reproduction and survival rates of individuals. We know this is true because certain mutations enable cells to multiply faster than their neighbors."

The idea of cancer as an evolutionary process was first summarized in 1976 by Dr. Peter Nowell of the University of Pennsylvania in a paper published in Science.

But putting the theory to the test requires monitoring the progression of genetic changes that occur in a tumor, a system for which the study of Barrett's esophagus is uniquely suited.

Barrett's esophagus, a precancerous condition caused by excessive acid reflux, is characterized by a progressive accumulation of genetic abnormalities in esophageal cells.

Reid's group has demonstrated that careful monitoring of patients with the disease can identify genetic abnormalities that put some patients at high risk for cancer. Because esophageal biopsies can be taken regularly over time, Reid and his collaborators have identified many of the mutations that must accumulate for certain cells in the tumor to evolve into rapid multipliers who outgrow their neighbors.

Weak-link search

Approaching the study of cancer with an eye toward evolution requires mathematical models that can simulate competition and look for possible weak links in the system.

Maley, who completed a master's thesis in evolutionary theory followed by a doctoral dissertation in theoretical biology - combining computer science with evolutionary theory - at the Massachusetts Institute of Technology, was ideally suited to join Reid's group on the modeling project.

His addition to Reid's group last summer reflects a shifting research climate in cancer biology.

"We're beyond the stage at which you can solve many problems the old way," Reid said. "We're in a new world of biology, in which we partner with mathematical scientists."

Reid and Maley say it is important to understand not only how cancer progresses, but also how cancers develop resistance to chemotherapy, which is an evolutionary process in itself.

"AIDS is a good example," Maley said. "If you treat AIDS with only one drug, resistance develops because the drug selects for those variants of the virus whose growth is unaffected by the drug and allows them to multiply. That's why most people are now treated with combinations of drugs."

Drug resistance also can be a problem for cancer treatment. Because tumors consist of a variety of cell types, some may be resistant to the drug and proliferate even in its presence.

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