October 1, 2004

Study leads to new colon cancer clues

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Vanderbilt researchers Richard Robinson, Brenda Crews, center, and Annette Oeser were honored at the inaugural Research Staff Awards luncheon last week.

Study leads to new colon cancer clues

Researchers at Vanderbilt University Medical Center have provided the first evidence that blocking a cellular receptor can inhibit the development of pre-cancerous colon polyps in mice.

The receptor, called PPARdelta, plays an important role in development, wound healing and fat metabolism. In the September issue of the journal Cancer Cell, the Vanderbilt scientists reported that they could inhibit polyp development in mice by “knocking out” the PPARdelta gene.

If confirmed in humans, blocking PPARdelta could provide a way to stop or prevent colorectal cancer, which kills more than 50,000 Americans annually, said Raymond N. DuBois, M.D., Ph.D., Hortense B. Ingram Professor of Molecular Oncology and the paper’s senior author.

PPAR stands for peroxisome proliferator-activated receptor, a family of three “transcription factors” that serve as on/off switches for a wide variety of genes.

In August researchers at the Salk Institute in La Jolla, Calif., reported that activating PPARdelta in mice stimulated changes in muscle fibers that enabled the animals to run “marathons” and eat a high-fat diet without gaining weight. A drug that turns on PPARdelta is being tested in patients with fat metabolism disorders.

However, when the drug was given to a strain of mice with a genetic mutation that makes them susceptible to developing pre-cancerous intestinal polyps, both the number and size of polyps increased significantly, DuBois and his colleagues reported last February in Nature Medicine. The same mutation is found in 80 percent of patients with colorectal cancer.

The findings suggest that drugs that activate PPARdelta “may encourage abnormal cell growth in certain populations at risk for colorectal cancer,” DuBois cautioned.

DuBois is internationally known for his pioneering studies linking the development of colorectal cancer to the cyclooxygenase-2 (COX-2) enzyme. COX-2 is a major target for drugs that relieve the pain and inflammation of arthritis, but COX-2 gene expression is also elevated in a variety of malignancies including colorectal tumors.

COX-2 generates several potent, hormone-like substances called prostaglandins that play a role in a wide variety of physiological functions. One of them, prostaglandin E2 (PGE2), has been specifically linked to the development of colon polyps.

The current study tested the effect of PGE2 in mice with the mutation that made them susceptible to polyps. Administration of the prostaglandin dramatically increased the number of intestinal polyps.

The animals were then crossed with mice without the PPARdelta gene. This generated animals with the propensity to develop colon polyps but lacking PPARdelta. When PGE2 was given to these mice, “we didn’t seen any increase in polyps,” DuBois said.

“Our results identify PPARdelta as a critical downstream mediator in PGE2-stimulated promotion of colorectal tumor growth,” the researchers concluded.

A drug that blocks PPARdelta has been developed in France, and the Vanderbilt researchers hope to test it in mice to see if it has the same effect as knocking out the gene. “We’ve been carefully examining drugs which inhibit COX-2,” DuBois explained. “Now we can really focus on key components of the downstream pathway.”

The research could lead to more specific — and safer — ways to prevent colorectal cancer. In addition to generating PGE2, the COX-2 enzyme produces another prostaglandin that blocks clot formation and dilates blood vessels. Long-term, high-dose use of the COX-2 inhibitor Vioxx has been linked to high blood pressure and an increased risk of serious heart problems in some patients.

The study’s lead author was Dingzhi Wang, Ph.D., research associate professor of Medicine.

Other members of the research team were Haibin Wang, Ph.D., Qiong Shi, Sharada Katkuri Sanjoy K. Das, Ph.D., and Sudhansu K. Dey, Ph.D., of Vanderbilt; and Walter Walhi, Ph.D., and Beatrice Desvergne, Ph.D., of the University of Lausanne, Switzerland.

The study was supported by the National Institutes of Health, the National Colorectal Cancer Research Alliance and the T.J. Martell Foundation.