Photo by Barbara Berg
A new Hutch study may help overcome one of the biggest challenges in colorectal cancer prevention research by shortening the time it takes to evaluate the impact of diet and other behaviors on cancer risk.
Researchers in the Cancer Prevention Research Program hope to identify an early marker for colorectal cancer, which could reduce the time it takes to identify foods, drugs or activities that cut cancer risk.
Progression toward colorectal cancer, a disease that will strike about 130,000 Americans this year, is typically monitored by looking for the formation of slow-growing polyps, potentially cancerous growths on the intestinal lining.
Because polyps can take years to grow to a detectable size, such research studies are long and expensive.
Dr. Rebecca Rudolph, a staff scientist in the Public Health Sciences Division, and collaborators hope to identify an earlier marker that will speed prevention studies and may also provide clues about the earliest steps in colon cancer development.
Potential early marker
Their study focuses on a potential early marker called aberrant crypt foci (ACF), clusters of abnormal cells that form patches on the intestinal lining.
Rudolph said that while there is evidence from animal studies to suggest that ACF are precursors of colon polyps, there is little known about how these polyps develop in humans.
"We'd like to know whether people who develop polyps have more or larger ACF, but we need to devise better methods for visualizing them," she said.
Dr. Johanna Lampe, a PHS investigator and Rudolph's collaborator on a related project, says that because colon polyps can take many years to develop, an early marker like ACF would be ideal for intervention studies.
"Right now one of the few endpoints we have in assessing whether a dietary intervention for reducing cancer risk works is to look at polyps," Lampe said.
"One big issue with regard to studies that involve colon polyps is that we have to do very long-term studies which are expensive and require a lot of resources," she said.
"An earlier measure, or endpoint, for these trials would be a great help."
Rudolph is working with Dr. Jason Dominitz, an assistant professor of medicine and an attending gastroenterologist at the Seattle Veterans Affairs Medical Center, to develop an endoscopic procedure - one that uses an instrument to examine the interior of the colon - for visualizing ACF.
Their strategy involves a modification of an endoscopic technique called colonoscopy. Colonoscopy allows the entire large intestine-which consists of the colon and rectum-to be visualized with a thin, flexible tube equipped with a tiny camera. Forceps can be passed through the tube to sample or remove abnormal growths for subsequent laboratory analysis.
A related technique, called flexible sigmoidoscopy, uses a shorter tube that allows visualization only of the rectum and lower portionof the colon.
Dominitz, also an affiliate investigator in the Hutch's Clinical Research Division, uses a magnifying colonoscope to visualize ACF, which are much smaller than polyps.
For their initial study, supported by Hutchinson Center pilot grant funds, Rudolph and Dominitz recruited 20 Veterans Affairs Medical Center patients scheduled for elective colonoscopy.
"Most of the study participants had been diagnosed with polyps previously and were undergoing colonscopy to determine whether new polyps had developed," Rudolph said.
"We were able to complete our procedure for visualizing ACF immediately after the colonoscopy."
The cells that line the large intestine derive from pockets in the intestinal wall called crypts. Each crypt contains self-renewing stem cells at its base, which continually produce new lining cells that migrate upward.
Normal lining of the colon has a smooth, uniform appearance, but some individuals have raised, irregular patches of cells known as ACF that may result from abnormal cells that migrate up from the crypt.
Scientists speculate that these cells, after accumulating a number of genetic changes, develop into polyps that may become cancerous.
Rudolph said that the earliest results of their ACF work have been encouraging, but that more work is needed to improve the accuracy of the technique.
"We've been able to visualize ACF, and after examining the biopsy samples of normal tissue and ACF in the lab, we've demonstrated a high level of sensitivity-meaning that we're picking up very few false negatives," she said.
"The challenge has been that we have a high false-positive rate, so we are working on modifying the procedure to make it more specific."
After they are confident that the technique works, Rudolph said, the next step will be to determine whether some aspect of ACF is strongly associated with the presence of polyps.
"We are planning a case-control study to investigate whether persons with polyps have larger or more numerous ACF than those who do not have polyps," she said.
Rudolph and Lampe also are working with Drs. Jeannette Bigler, John Potter and Ziding Feng to develop strategies for comparing gene expression in normal crypts with ACF. Those studies will use DNA microarrays - chips that analyze thousands of genes simultaneously - to identify a subset of genes that may provide clues to ACF origin.
How Do Scientists 'See' ACF?
For visualization of aberrant crypt foci (ACF), a spray catheter is threaded through a magnifying endoscope so that a non-toxic blue dye can be sprayed inside the colon. After excess dye is washed out, a magnifiying colonoscope is used to look for ACF.
The images are displayed on a video monitor, allowing a physician to adjust the position of the colonoscope inside the patient. Forceps can be used to remove suspected ACF and normal tissue for microscopic analysis.