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Research suggests new avenue for stopping, preventing colon cancer

NASHVILLE, Tenn. Researchers at the Vanderbilt-Ingram Cancer Center (VICC) have provided the first evidence that blocking a cellular receptor can inhibit the development of pre-cancerous colon polyps in mice.

The research suggests a new avenue for stopping or preventing colon cancer, which kills more than 50,000 Americans each year, said the paper's senior author, Raymond N. DuBois, M.D., Ph.D., Hortense B. Ingram Professor of Molecular Oncology and the VICC's associate director for Cancer Prevention and Control.

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

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
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Contact: Cynthia Floyd Manley
cynthia.manley@vanderbilt.edu
615-936-5711
Vanderbilt University Medical Center
20-Sep-2004


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