New Pathway Found to Colon Cancer

EMBARGOED FOR RELEASE: 24 May 5:00 PM EST

Contacts at the Eccles Institute of Human Genetics, University of Utah:Jun Liu, Ph.D., 801-585-6224Kristen Kamerath, public relations, 801-585-0538Additional contact: Nori Matsumani, M.D., Ph.D., 510-494-4056

New Pathway Found to Colon Cancer

SALT LAKE CITY, Utah -- A colon cancer gene, one that is responsible for 80% of cases of the disease, was discovered 10 years ago by Raymond White, Ph.D., a geneticist at the University of Utah. Since then, scientists have been picking apart the biological systems involved in colon cancer, looking for the triggers that cause cancer to develop. Recently, scientists at the University of Utah were again rewarded when they uncovered a new pathway that helps control cell growth cycles. A research team led by Nori Matsunami, M.D. Ph.D., discovered that p53, a prominent tumor suppressor in many cancers and cell types, turns on a pathway that involves APC, the protein implicated in most instances of colon cancer. Study results will be published in the May 25 issue of the journal Molecular Cell.

The pathway to colon cancer includes many complex connections that set off certain critical events. This study adds a new twist by showing that turning on the p53 tumor suppressor gene activates a previously unknown pathway that, via APC, reduces levels of beta-catenin, a protein that turns on cell growth cycles. If this pathway is broken, such as by a mutation that inactivates APC, then beta-catenin will keep activating the cell growth cycle. This can lead to uncontrolled cell growth that creates cancerous tumors.

This mechanism of regulating cell growth caused by beta-catenin represents a new target for developing therapeutic drugs for colon cancer and perhaps for other cancers as well, since beta-catenin is implicated in additional cancer types, including desmoid, hepatocellular, kidney, medulloblastoma, melanoma, ovarian and pancreatic.

Jun Liu, Ph.D., a co-author on the study, says the research team's overall goal is to comprehensively understand APC's function so they know what role it plays in the cancer development pathway. However, he notes this is easier said than done with a complex disease like colon cancer. "We never know if we've discovered everything that a single protein does -- that's a very difficult question to answer," Liu comments.

Lead study author Matsumani, notes that APC was previously known to be involved in regulating beta-catenin in a separate pathway that does not involve p53. However, when the research team discovered an interaction between APC and an entirely new protein (one that ended up belonging to the new p53 pathway) they started looking for another pathway. "Interestingly, [this new protein] was known as a p53-mediated regulator of cell-cycle arrest and tumor suppression. On the other hand, beta-catenin was known as an activator of cell growth. We hypothesized that APC might provide a new link between p53 and cell-cycle regulation through degradation of beta-catenin," Matsumani says.

Announcements of gene discoveries for various diseases happen frequently, often stating that the scientists' next step will be to figure out what the gene does and then to devise a drug to treat the disease. In the case of colon cancer, this next step is hard, tedious work, because it is so complex. "Many changes happen when normal cells turn into malignancy. We need to explore and characterize the fundamental changes that define the critical stages of cancer development," Matsumani says.

Colon cancer kills 60,000 people in the United States annually, second only to lung cancer. Only 20% of the population gets the appropriate level of screening, which, thanks to genetic research, can show the need for early treatment that will eliminate disease risk.

Nori Matsunami, a research assistant professor in the department of oncological sciences, is currently on sabbatical from the University. Jun Liu, another member of the research team, recently received his Ph.D. from the University. Raymond White, the original discoverer of the APC gene, is also a co-author of the study. Dr. White is currently on sabbatical from the University.

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A summary of recent research on beta-catenin pathways, written by Paul Polakis of Genentech, will accompany publication of the study in Molecular Cell.