Sep. 22, 1999 CHAPEL HILL - A study of fruit flies by scientists at the University of North Carolina at Chapel Hill may yield new clues to human colon cancer development.
A report of the study, the cover story for the September 20 issue of the Journal of Cell Biology, focuses on the tumor suppressor protein adenomatous polyposis coli, or APC. Originally identified in people with familial colon cancer, APC mutations are found in a majority of colon tumors.
According to senior study author Dr. Mark Peifer, UNC-CH associate professor of biology and a member of UNC Lineberger Comprehensive Cancer Center, APC plays an important role within cells to help destroy another protein, beta catenin. His research confirms that in fruit flies (Drosophila), it functions against a very similar protein, Armadillo.
"Beta catenin transmits signals from the cell surface to the nucleus," Peifer explains. "Normally, beta catenin levels in colon cells are very low because it gets rapidly destroyed."
Studies have found that mutations to APC disrupt the beta catenin destruction signaling machinery. Genes along the pathway are fixed permanently to "ON" and beta catenin cellular levels rise. In the cell nucleus this triggers a molecular chain of events that in mammals leads to cell proliferation and tumor formation.
"During normal development, cells are talking to one another, sending signals to a neighbor for a short period of time, at the right time and at the right place. Occasionally, a mutation can switch the signaling pathway to an 'ON' state for good. And that often causes trouble," Peifer says.
"The cancer connection in the signaling pathway we study was first made in colon cancer, one of the most important human malignancies because it is one of the most prevalent," Peifer notes. "It's probably the most prevalent that's not easy preventable. If people didn't smoke, colon cancer might be the most common malignancy."
In the new study, Peifer and his colleagues at UNC and Northwestern University point to another cellular role for APC, one that also may apply to colon cancer. Building on work done by others at Princeton University, they have identified a gene in fruit flies that encodes a second fruit fly APC, Drosophila APC2 . The mutations they made in those genes yielded both surprising and not-so-surprising results.
"We learned, not surprisingly, that if you eliminate the destroyer of Armadillo, its levels go up and you activate the signaling pathway. It confirmed what we thought was true is true," Peifer says.
"We also learned that this pathway doesn't just target the nucleus," the UNC biologist adds. "Signals from APC2 may affect the cytoskeleton, the part of the cellular machinery that forms the cell's skeleton."
The researcher says this finding supports a theory of Stanford University's W. James Nelson that APC mutations' effects on the cytoskeleton may lead to tumors. In the colon, mutations in APC signaling would prevent colon cells from migrating upward from the glandular crypts within the intestinal mucus membrane to the villi, tiny projections on the surface.
"The crypt is an environment where cells are told to proliferate. So if cells are kept in that environment longer, you might get more cell proliferation, possibly leading to tumor formation. This is further evidence for that idea," Peifer says.
Peifer's collaboration with colleagues in The Netherlands has identified two APC protein families in human cells.
"We're now interested in trying to understand how different APC members in fruit fly and mammalian cells might influence the cytoskeleton," the researcher says. Additional studies will involve the crystal structure of beta catenin, recently solved at Stanford University.
"That gives us a 3-dimensional picture of the protein, so we can ask how does our protein dock on other proteins," he says. "And if we understand those interactions, we can go in and block them. And if we do that in colon cells, then we might disrupt tumor development."
He adds: It's terrific to feel like we're really making a genuine impact on clinically relevant work. The work we're doing on understanding this pathway, the precise details of how proteins work and interact, will allow us to conceive rational ways to attack problems in its signaling activity."
Peifer's UNC co-authors include Drs. Brooke M. McCartney, Catherine Kirkpatrick, and Annette Bass. Northwestern University Biochemistry, Microbiology, and Cell Biology collaborators are Drs. Herman A. Dierick, Melissa Moline, and Amy Bejsovec.
The research was funded by grants from the National Institutes of Health, the U.S. Army Breast Cancer Research Program, and the National Science Foundation.
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