Dec. 17, 2001 Researchers at Jefferson Medical College may have figured out one way in which a mutation in a gene thought to be responsible for colon cancer may actually cause the disease in the first place.
They showed in the laboratory that this gene, APC, normally limits the expression of a protein, survivin, which prevents stem cells in the colon from dying. When APC is altered, survivin works overtime and stem cells in the colon, instead of dying, overpopulate, resulting in cancer.
The scientists, led by Bruce M. Boman, M.D., Ph.D., director of the Division of Genetic and Preventive Medicine at Jefferson Medical College and director of the Gastrointestinal Cancer Program at the Kimmel Cancer Center of Thomas Jefferson University in Philadelphia, studied survivin, which is overexpressed in colon cancer. Survivin prevents programmed cell death, or "apoptosis," the process by which cells normally die. Rather than dying on schedule, cancer cells are instead growing out of control. This makes sense, says Dr. Boman, since cancer cells are thought to be immortal. Dr. Boman and his co-workers showed that the APC gene controls the amount of survivin by shutting down its production.
"We have evidence that APC mutation leads to more stem cells in the colon of patients with FAP," he says, referring to familial adenomatous polyposis, a form of inherited colon cancer marked by excessive polyps in the colon. "However, we don't know the mechanism. Abnormal regulation of survivin provides one mechanism." The researchers report their findings Dec. 15 in the journal Cancer Research.
Previous evidence from Dr. Boman's research indicated that FAP patients may be predisposed to cancer because processes that regulate the number of adult stem cells in the colon have gone awry.
Stem cells lie in the bottom of tiny "crypts" in the epithelium, or lining, of the colon. Stem cells produce daughter cells that proliferate, eventually making their way to the top of the crypt, where they become specialized colon cells. According to Dr. Boman, FAP is characterized by a change in the pattern of proliferating daughter cells. That is, the so-called "cell proliferation zone" shifts from the bottom toward the top of the crypt. But characterizing the cellular mechanisms that underlie this change has been difficult.
In the study, the scientists examined normal colon cells with normal APC genes and, they anticipated, little or no survivin protein. They were surprised to find survivin in the cells at the bottom of the colon crypts.
"That supports our idea that APC is shutting down survivin production," Dr. Boman says. "As the APC concentration increases going up the crypt, it inhibits survivin expression."
Because mutant APC can't shut down survivin, apoptosis is prevented and stem cells are overproduced. This may be a key mechanism in the origin of colon cancer. Next, the Jefferson scientists would like to determine how to target this mechanism and prevent stem cell overpopulation. "If we could find a way to attenuate survivin production, perhaps it could be a basis for colon cancer therapy," Dr. Boman explains. "It might potentially work for other cancers as well."
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