The pathway is associated with a tumor suppressor gene called APC, identified by the Hopkins team in 1991 and found to be mutated in 85 percent of all colon cancers. In the new studies, the teams found that the mutation of APC results in the overactivation of two other genes called B-catenin, previously associated with APC by Hopkins researchers, and Tcf, recently isolated by the Netherlands researchers.
"These three genes are part of a pathway--an interconnected series of genes that communicate with one another through the production of proteins to regulate the growth and death of cells," says Kenneth Kinzler, Ph.D., associate professor of oncology at the Hopkins Oncology Center and co-investigator in these studies. "APC is actually a negative control mechanism, or "off switch," for B-catenin and Tcf. When the APC gene is mutated, it cannot perform this function," he says. "Without APC to regulate them, proteins produced by the B-catenin and Tcf genes continue to signal cells to grow, but not to die. This alteration of the cell cycle eventually results in colon cancer."
"In most colon cancers, the pathway is overactive due to APC mutation, and cells never receive the signal to die," says Patrice J. Morin, Ph.D., of the Howard Hughes Medical Institute at the Johns Hopkins Oncology Center and lead author of this study. "In colon cancers that do not have APC mutations, we found a significant number of B-catenin gene mutations, which appear to result in similar overactivation of the pathway."
Kinzler and his colleagues believe the malfunctioning pathway could be corrected with drugs known as "inhibitors" that block B-catenin and Tcf gene function--the role the APC gene normally plays. "It is much easier to block the function of B-catenin and Tcf than to try to restore the missing function of APC. This is what makes the discovery of this pathway so exciting. Not only do we understand what is happening, but we may actually be able to do something about it," says Kinzler.
Kinzler believes this same approach also may be beneficial to people diagnosed with an inherited genetic disease known as Familial Adenomatous Polyposis (FAP). This condition is characterized by the formation of hundreds to thousands of polyps in the colon, some of which eventually become cancerous. Several years ago, the Hopkins researchers linked the development of FAP to mutations of the APC gene.
Approximately 131,000 new cases of colon cancer will be diagnosed in the United States this year, and approximately 37,000 people will die from the disease. Colon cancer is the third most common cancer diagnosed in both men and women.
In addition to Kinzler and Morin, other participants in this research include Bert Vogelstein, M.D., of the Howard Hughes Medical Institute at the Johns Hopkins Oncology Center; Andrew B. Sparks, Ph.D., of the Johns Hopkins Oncology Center; and Hans Clevers, M.D., Ph.D., Vladimir Korinek, and Nick Barker, M.D., from University Hospital in the Netherlands.