NEW YORK, March 20 (Reuters) -- In the search to identify the factors that contribute to cancer, researchers have identified the "smoking gun" of colon carcinoma -- the protein that gives rise to tumors when molecular machinery goes awry.
The protein is called beta-catenin and it plays a major role in the cascade of events that leads to colon cancer -- and probably melanoma as well, according to a trio of studies in this week's issue of Science.
The finding may help drug companies find new ways to combat colon cancer, and possibly other types of cancer as well, according to Dr. Mark Peifer, a researcher at the University of North Carolina at Chapel Hill.
"I'm very excited about this," said Peifer, who wrote an editorial accompanying the studies. "It promises the possibility to really go to look for agents that interfere with this pathway in one way or another."
The reports link beta-catenin to a specific gene mutation found in up to 80% of people who develop colon cancer spontaneously, and in 100% of those with familial adenomatous polyposis (FAP), an inherited condition in which hundreds to thousands of intestinal polyps develop in young adulthood, vastly increasing the risk of colon cancer.
Now, the new reports confirm that the genetic defect, found in the adenomatous polyposis coli (APC) genes, allows levels of beta-catenin to soar. The protein then interacts with transcription factors, compounds that regulate genes. The researchers believe this process releases the "brakes" on cellular growth, allowing a cell to wildly proliferate and become a polyp, which then goes on to become cancerous.
About 50% of all people will develop colorectal polyps in their lifetime because of a mutation in an APC gene -- though not all will have other mutations that result in colorectal cancer.
"A possible avenue is to look for drugs that block the interaction between beta-catenin and transcription factors," said Peifer. "If one could block that interaction that would presumably shut down the pathway," Peifer said.
The reports also found that a mutation in the beta-catenin, itself, can lead to rising levels. Apparently, an abnormal beta-catenin protein won't trigger a feedback mechanism to halt its own production. Thus, there are two different pathways for colon cancer to develop.
The studies were conducted by researchers at the University Hospital in Utrecht, the Netherlands; Howard Hughes Medical Institute, John Hopkins Oncology Center in Baltimore, Maryland; the National Cancer Institute in Bethesda, Maryland; and Onyx Pharmaceuticals in Richmond California.
The results are some of the most important findings in terms of the cause of colon cancer, according to one study co-author, Dr. Paul Polakis, research director at Onyx Pharmaceuticals.
"It's highly significant with regards to colon cancer because it confirms our original hypothesis that beta-catenin is indeed the problem -- it lets us now know what the target is in colon cancer and where to look if we want to interfere with colon cancer."
And beta-catenin mutations were also found in melanoma, a relatively rare but dangerous type of skin cancer.
"A significant percent of melanomas have mutated beta-catenin as well, so it makes this a more widespread general phenomenon in cancer," said Polakis. "It will not surprise me at all if we see it in breast cancers as well."
SOURCE: Science (1997;275:1752-1753, 1784-1787, 1787-1789, 1790-1792)
