Key stimulator of colorectal cancer identified
A new research study identifies a molecule that promotes one of the most deadly cancers in humans and reveals the molecular mechanisms underlying the protective effects of nonsteroidal anti-inflammatory drugs (NSAIDS) against the disease. The research, published in the September issue of Cancer Cell, identifies potential targets for future therapeutics aimed at the prevention and treatment of cancer of the colon and rectum.
Colorectal cancer (CRC) is the second most common cause of death due to cancer for men and women in the United States It has been known for some time that NSAIDS and other cyclooxygenase (COX) inhibitors reduce the risk of CRC. However, the exact mechanisms of this protective action are unclear. PGE2 is a metabolite of COX that is elevated in CRC and has been implicated in disease development and progression. Peroxisome proliferator-activated receptor d (PPARd), a regulator of cell survival, has also been linked to CRC. Dr. Raymond N. DuBois from the Department of Medicine at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center in Nashville, Tennessee and colleagues investigated whether the ability of PGE2 to promote CRC is dependent on PPARd.
The researchers found that PGE2 indirectly activates PPARd via a signaling pathway that promotes cell survival and polyp formation. Polyps are abnormal growths in the colon and rectum that are believed to be an early stage of CRC. In a mouse model system for studying polyp formation, PGE2 treatment induced an increase in the number and size of intestinal polyps. Importantly, this effect of PGE2 was not observed in these mice when they lack PPARd.
"Our results identify PPARd as a critical downstream mediator in PGE2-stimulated promotion of colorectal tumor growth," says Dr. DuBois. "They suggest that PPARd is an important pro-cancer factor in CRC, and that agents which stimulate PPARd may encourage abnormal cell growth in certain populations at risk for CRC. In addition, it is possible that blocking PPARd might prove useful for prevention and/or treatment of CRC."
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