Jefferson scientists use computer model to show cancer may be a stem cell disorder

November 30, 2001

Cancer may be a disease of stem cells gone awry.

Researchers at Jefferson Medical College have developed a computer model showing that a form of inherited colon cancer, familial adenomatous polyposis, or FAP, may begin when processes that regulate adult stem cells in the colon go out of control.

If the model is correct, it may explain how cancer begins and may suggest a potential target at which to aim drugs to stop it.

"This model suggests that the change in cell growth patterns that represents the initiation stage of colorectal cancer is due to an increase in the number of stem cells in the colon epithelium," says 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, who led the work.

"This provides evidence that an increase in the number of stem cells triggers colon cancer," says Dr. Boman. "The broad implication is that cancer may be a stem cell disorder."

Dr. Boman and his co-workers report their work December 1 in the journal Cancer Research.

Stem cells that lie in the bottom of tiny "crypts" in the epithelium of the normal colon produce daughter cells that proliferate, eventually making their way to the top and differentiating into specialized colon cells. According to Dr. Boman, colon cancer initiation in FAP, on the other hand, is marked by a change in the pattern of proliferating daughter cells. Namely, the cell proliferation zone shifts from the bottom toward the top of the crypt. But characterizing the cellular mechanisms that underlie this change in cell growth has been difficult.

Dr. Boman and his co-workers studied data regarding the proliferative change that occurs in FAP colon tissue when cancer begins. "The tissue appears normal in patients with an inherited mutation in the APC gene, which is the gene altered in FAP," he says. "But when you label the cells in the colon epithelium, there is a shift in the proliferative zone from the lower crypt to the top of the crypt." Sporadic colon cancers have the same mutation as the hereditary form of the disease.

"This genetic change they carry is the initiating event that triggers colon cancer," Dr. Boman says of the APC mutation. "No one can explain how the tissue change - normal to cancer - occurs on the basis of the genetic change. We set out to explain the cellular mechanism involved that might link the two."

Dr. Boman and his co-workers decided to create a computer model because the dynamics of the colonic crypt and colon tissue are complex and standard experimental methods have limitations, he explains. They first developed a computer model that successfully simulated growth patterns in the normal colon. They then changed the model parameters to see if they could get a computer simulation of the proliferative shift in the colon cells that occurs when cancer begins. But this initially proved difficult.

"We changed the rates of the cell cycle, the rate of programmed cell death and other variables but didn't get a fit with what the biological FAP data showed," he says. When they began increasing the number of stem cells at the bottom of the crypt model, they suddenly began to see a shift that mimicked what is seen biologically.

"Now we can use our model to attempt to explain the origin of the first known tissue change in the development of colon cancer."

Boman and his co-workers used FAP as a model because both the genetic and tissue changes are well characterized. FAP is characterized by the formation in early adult life of hundreds to thousands of polyps, or benign tumors, in the colon. These invariably develop into cancer if they are not snipped out. Patients frequently must have their colons removed as well.

The model may be relevant to other cancers - including other hereditary cancers, he notes.
Additional Contact: Phyllis Fisher
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Editor's Note: This information is embargoed for release on Nov. 30, 2001 at 6 p.m. ET

Thomas Jefferson University

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