July 31, 1998
La Jolla, CA – Although it’s now common wisdom that dietary fat is related to some cancers, medical researchers have not understood the underlying mechanisms. In research reported in the September 1 issue of Nature Medicine, scientists at The Salk Institute for Biological Studies identify a molecular link between fat metabolism and colon cancer. The results may also be relevant to breast and prostate cancer, common cancers that are also associated with dietary fat.
“The identification of a specific molecular fat sensor that contributes to human cancer provides us with a direct opportunity to develop new classes of pharmaceutical drugs,” according to Salk Professor Ronald Evans, senior author of the study.
The link, a molecule named PPAR gamma, was shown in previous work from Evans’ laboratory to aid in the formation of fat cells and storage of fat. In the current study, mice given compounds known to stimulate PPAR gamma developed three times as many colon polyps as their litter mates. The strain of mice used in the experiments are predisposed to develop colon polyps and are frequently used as a model for human familial colon cancer.
On the molecular level, PPAR gamma acts as a fat sensor – hormones, drugs, and dietary fats attach to the sensor to exert their influence. Earlier work had shown that PPAR gamma and its hormone serve as a master regulator of the formation of body fat.
The current study used synthetic hormones to attach to PPAR gamma; mice given these hormones developed polyps at a rate comparable to mice in other studies that were maintained on high-fat diets.
“The results are highly suggestive of PPAR gamma mediating the connection between fat intake and cancer promotion,” said Enrique Saez, postdoctoral fellow and lead author of the study. “Presumably fat stimulates PPAR gamma to regulate genes that control cell division, cell death or other aspects of tumor development. The next step is to identify these genetic targets.”
Because PPAR gamma also is found in breast and prostate cancer cells, the investigators believe the current study has implications for understanding the link between dietary fat and these two common cancers.
In addition to their relevance to tumor development, the findings raise questions about medical treatments currently used for diabetes. Troglitazone, marketed as Rezulin and one of the most commonly prescribed drugs for non-insulin dependent diabetes, stimulates PPAR gamma and is the same hormone used by the Evans group.
“These findings raise the issue of whether troglitazone treatment might increase risk for colon cancer,” according to Peter Tontonoz, M.D., postdoctoral fellow and a co-author of the study. “It’s an issue that should be examined, particularly in patients with a family history of colon cancer.”
He added that troglitazone treatment did not increase colon polyps in normal mice and therefore might not present a risk to diabetes patients with no family history of colorectal cancer.
Paradoxically, when the investigators treated colon cells in tissue culture with PPAR gamma stimulators, tumor cells actually lost some of their cancer-like properties and began to revert to normal. A research group from the Dana Farber Cancer Institute in Boston reports similar results with cultured cells in the same issue of Nature Medicine and advocates using PPAR gamma stimulators to treat colon cancers. “We’re not sure why we should see this conflict between the in vitro and in vivo results,” said Evans. “But we believe that the animal results are probably more relevant to what goes on in human beings and caution against using PPAR gamma stimulators in humans.”
A third paper in the journal from a team at Institut Pasteur in Lille, France reports results in mice that agree with the Salk findings. Salk co-authors include research technicians Michael C. Nelson, Jacqueline G. A. Alvarez and Tze Ming U. Collaborators include Stephen M. Baird, M.D., a surgical pathologist at the University of California, San Diego; and Vilmos A. Thomazy, M.D., a pathologist at the University of Texas at Houston Medical School. Evans is a Howard Hughes Medical Institute investigator, and Saez was supported by the Susan G. Komen Breast Cancer Foundation.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution conducting basic science research dedicated to the improvement of human health and improving the quantity and quality of the world’s food supply.
Its two main fields of concentration are neuroscience and molecular-cellular biology and genetics.