December 15, 2006

Lipid disorder drugs may increase cancer risk: study

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Raymond DuBois, M.D., Ph.D., left, and Dingzhi Wang, Ph.D., are studying whether a class of drugs that treat obesity and elevated cholesterol may increase colon cancer risk.
Photo by Gwyneth McEuen

Lipid disorder drugs may increase cancer risk: study

A class of drugs under investigation for treating obesity and disorders of fat metabolism (such as elevated cholesterol) may increase colon cancer risk, a new study by Vanderbilt-Ingram Cancer Center researchers suggests.

In the Dec. 12 issue of the Proceedings of the National Academy of Sciences, Raymond DuBois, M.D., Ph.D., and colleagues demonstrate that a drug that blocks PPAR-delta, a cellular protein involved in fat metabolism, promotes tumor formation in mice.

The peroxisome proliferator activated receptors (PPARs) are a family of transcription factors that control the expression of a number of genes. Fat intake activates one member of this family, called PPAR-delta, which then turns on genes that aid in the breakdown and usage of fat by the body.

Because of its role as a “lipid sensor,” drugs that activate PPAR-delta are being investigated as therapies for a host of conditions, including obesity and dyslipidemias such as elevated cholesterol.

There is, however, a potentially deadly drawback. PPAR-delta is elevated in the majority of human colon cancers and in animal models of colorectal cancer, suggesting that the receptor plays a role in cancer risk.

PPAR-delta appeared on DuBois' radar during experiments he was conducting to determine the role of the pro-inflammatory COX-2 pathway in colon cancer.

“We noticed that if we treat mice with a product of this pathway, namely prostaglandin E2, that we saw an activation of the PPAR-delta pathway,” said DuBois, director of Vanderbilt-Ingram and professor of Medicine, Cancer Biology, and Cell and Developmental Biology.

Subsequent studies continued to build a case for PPAR-delta's involvement in colon cancer. DuBois and colleagues found that a drug that increases the activity of PPAR-delta promotes tumor formation in mice. In a separate study, they found that deleting the gene for PPAR-delta in colon cancer-prone mice led to a reduction in the number and size of intestinal polyps, growths that are often precursors of colon cancer. However, they still had not found the definitive link to ensure that PPAR-delta actually mediated the observed effects.

DuBois and Dingzhi Wang, Ph.D., research professor of Medicine and first author on the paper, designed the current study to fill in that missing bit of information. In this study, the researchers administered the drug that activates PPAR-delta to colon cancer-prone mice lacking PPAR-delta.

“We found that if we knock out the receptor and then treat with the drug, we don't see an increase or acceleration of tumor growth,” DuBois said. “So we feel pretty confident that this effect is due to the presence of the receptor.”

The researchers also identified a potential intermediary in PPAR-delta's cancer promoting effects. Activating PPAR-delta stimulated the production of a growth factor, called VEGF (vascular endothelial growth factor). VEGF can then bind to tumor epithelial cells and prevent “programmed cell death,” a mechanism that helps keep cell growth in check.

The findings raise concern about drugs designed to increase PPAR-delta activity.

“The story is still developing” DuBois said, “but this certainly does raise some concern and should stimulate a more careful assessment of people who are treated with these drugs to make sure that it's not causing an increased cancer risk.”

DuBois noted that the work also may provide insight into the relationship between obesity and cancer. “There is a lot of evidence that people with a high body mass index have a higher risk for some cancers,” he said.

“It has not escaped our attention that this 'lipid sensor' might have some role in that — that it could be a link between obesity and cancer.”

Not all “doom and gloom,” DuBois' work also suggests that inhibiting the activity of PPAR-delta might have cancer-preventive effects in the future.

Even so, DuBois is most excited about the new information revealed in this study about how tumor cells interact.

“I think the more we understand about the interplay between the tumor stromal cells and tumor epithelial cells, the better off we will be in getting more definitive treatments.”