Activation Of Receptor Ups Development Of Precancerous Intestinal Polyps

However, they also raise caution about an increased risk of colorectal cancer among people who take drugs that activate this receptor. Such drugs are currently in clinical development to treat obesity and atherosclerosis.

The researchers report their findings Feb. 2 in the online version of the journal Nature Medicine. The paper is scheduled for publication in the print edition next month.

The work was funded in part by the National Colorectal Cancer Research Alliance (NCCRA), an initiative led by NBC's Katie Couric, Lily Tartikoff and the Entertainment Industry Foundation. Other support came from the T.J. Martell Foundation for Leukemia, and the National Cancer Institute.

The group found that among mice with a specific genetic mutation - one that is found among 80 percent of human patients with colorectal cancer - the incidence of larger colon polyps increased fivefold with treatment of a compound known to bind very specifically to the peroxisome proliferator-activated receptor delta (PPAR-delta).

"This is extremely significant because it is these larger polyps that are most likely to develop into intestinal cancer," said Raymond N. DuBois, MD, PhD, Hortense B. Ingram Professor of Molecular Oncology, a professor of Medicine, and associate director of cancer prevention, control and population-based research at Vanderbilt-Ingram.

The team became interested in PPAR-delta's potential role in colorectal cancer development after the observation that the receptor is overexpressed in most colorectal cancer tumors. As part of the lab's ongoing research into the enzyme cyclooxygenase-2 (COX-2) and its role in colorectal cancer, the group noted that PPAR-delta is activated by a COX-2 prostaglandin product. Raju Gupta, a Vanderbilt medical student and member of the DuBois' laboratory, reported these findings in the Proceedings of the National Academy of Sciences in 2000. Dr. Bert Vogelstein and colleagues at Johns Hopkins' Sidney Kimmel Cancer Center reported similar findings a year earlier in the journal Cell.

Evidence for a direct role for PPAR-delta in colorectal cancer has been mixed; however, the Vanderbilt-Ingram scientists noted, those studies did not test agonists (which activate receptors) that strongly bind to PPAR-delta without similar attraction to two other forms of the receptor, named PPAR-alpha and PPAR-gamma.

They selected a molecule for this work with high specificity for the delta version of the receptor, known as GW501516. They tested this ligand (a molecule that binds to a receptor) in mice with a known mutation in the Apc gene. "APC mutations are found in all individuals with an inherited form of colon cancer called familial adenomatous polyposis (FAP) and is seen in 80 percent of sporadic colorectal cancers, so the mutation is highly relevant to colorectal cancer in humans," DuBois said.

In line with published data, the untreated mice developed an average of 30 polyps in the small intestine and an average 1.4 polyps in the colon. Treatment with GW501516 led to a twofold increase in small intestine polyps and no change in colon polyps.

Because polyp size is an independent risk factor for progression to colorectal cancer, the scientists evaluated the data according to polyp size. Interestingly, this is where the treatment's effects were most dramatic - the mice treated with the PPAR-delta agonist developed five times more polyps larger than 2 mm. The polyps were examined under the microscope, and the polyps from the treated mice were much larger and showed more dysplasia (abnormal appearance) than those from the untreated mice. Dysplasia is known to be a precursor of malignancy.

The researchers conducted cell culture studies to eliminate any effects of GW501516 that were not related to PPAR-delta activation. They treated wild-type cells and cells engineered to remove the PPAR-delta gene. There was no change in cell proliferation; however, treatment with GW501516 significantly suppressed apoptosis (programmed cell death) in the wild-type cells but not in the cells lacking PPAR-delta.

"These results argue that PPAR-delta stimulates intestinal adenoma development and size by activating antiapoptotic pathways in intestinal epithelial cells," the researchers write. Because the cells avoid cell death, they have a survival advantage, DuBois further explained, suggesting that PPAR-delta may play a role in colorectal cancer not by initiating polyp development but by accelerating their growth.

Additional research is needed, including verifying the results in APC mutant mice which are engineered to eliminate the PPAR-delta receptor. However, the researchers noted, "PPAR-delta may be an attractive target for the development of small molecule antagonists as chemopreventive or chemotherapeutic agents for colorectal cancer."

Because the APC mutation is present in all individuals with FAP, this research suggests that patients with this inherited disorder should not take PPAR-delta agonists for other indications. The researchers also caution that because the mutation occurs in the vast majority of sporadic colorectal tumors, individuals with pre-existing polyps who take PPAR-delta agonists may also be at significantly increased risk for colorectal cancer.

In addition to Gupta and DuBois, co-authors are Dinghzi Wang, Sharada Katkuri (department of Medicine), Haibin Wang and Sudhansu K. Dey (departments of Pediatrics and Cell & Developmental Biology).

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The Vanderbilt-Ingram Cancer Center, part of Vanderbilt University, is one of only 38 National Cancer Institute-designated Comprehensive Cancer Centers in the United States and the only such center in Tennessee. For more information, visit http://www.vicc.org.