New Study Shows Steps Leading To Colon Cancer

March 21, 1997

CHAPEL HILL, N.C. -- New research done on insects in North Carolina and on human cells elsewhere has identified a key signaling mechanism required for normal embryonic development. When inappropriately activated, studies show, the mechanism turns healthy cells first into abnormal ones and then often into tumors.

"Our work, together with that of our colleagues, reveals for the first time the precise role of a key regulatory protein found in both insects and ourselves," said Dr. Mark Peifer, assistant professor of biology at the University of North Carolina at Chapel Hill. "We have found that this protein, called 'armadillo' in insects and 'beta-catenin' in humans, goes into the cell nucleus and helps regulate gene expression or, in other words, turns genes on and off."

In normal embryonic development, by switching genes on and off, the protein tells cells which tissues they should make and directs, for example, development of arms and legs, Peifer said. The

process occasionally goes awry, however, when beta-catenin becomes active in places where it should not. It then triggers cells to reproduce indefinitely, or it prevents them from dying, leading to benign tumors that can later become malignant.

"It is now clear that this sort of mistake underlies essentially all cases of colon cancer and many melanomas, a form of skin cancer difficult to treat," he said.

A report on the findings, supported by the National Institute of General Medical Sciences, appears in the March 21 issue of the journal Cell. Besides Peifer, UNC-CH authors are doctoral students Robert Cavallo and Joseph Loureiro. Other authors include Drs. Marc van de Wetering and Hans Clevers of University Hospital in Utrecht, Netherlands, and others at the National Cancer Institute and American and Northwestern universities.

Peifer, a member of the UNC Lineberger Comprehensive Cancer Center, also has a commentary in Friday's (March 21) issue of Science in which he discusses closely related papers on colon and skin cancer appearing in that journal.

"Science and detective fiction share many features: a mysterious event, suspects with motives and opportunity and a collection of evidence," Peifer wrote. "The best cases end with a smoking gun, clinching the guilt of a suspect. This issue of Science contains three such smoking guns ... firmly establishing beta-catenin as an accomplice in causing colon cancer and as a strong suspect in melanoma. As in many crimes, however, beta-catenin did not act alone but with a set of partners."

Describing work in fruit flies -- genetically similar to humans and far easier to work with -- the Cell paper explains the precise biochemical functions of armadillo, Peifer said. It turns out that the protein enters cell nuclei, combines with another protein called dTCF, latches onto DNA and becomes the equivalent of a light switch.

"Now that we understand what happens normally, we can imagine using fruit flies to search for and test potential drugs which might turn off or block the signaling pathway that leads to tumors," he said.

Fruit flies are far more important in biology and medicine than most people realize, Peifer said.

"Two years ago, the Nobel Prize in medicine and physiology went to three scientists who showed us that essentially the same cellular machinery that works in people works in fruit flies," the UNC-CH biologist said. "If we want to learn how our own cells operate, it is a lot easier and faster to do that in fruit flies than in humans or even mice."

The research published in Science involved Peifer's colleagues in the Netherlands as well as scientists at the Howard Hughes Medical Institute at Johns Hopkins University, Onyx Pharmaceuticals in Richmond, Calif., and the National Cancer Institute. He called it an example of how, when scientists collaborate and build on each others' findings, society benefits.

"The public supports basic research with its tax dollars, and scientists need to convey to them what they are doing and why," Peifer said. "We believe this work is a good example of how the investment pays off. It is extremely important to understand how cancer develops. Once we understand this, we can use the knowledge to develop more effective treatments."

University of North Carolina at Chapel Hill

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