Obesity researchers have been studying ways to turn the body’s energy-storing “bad fat” into energy-burning “good fat.” Now, scientists are reporting that the flip side of that approach could address a huge killer of cancer patients—the muscle wasting, emaciation, and frailty known as cachexia, which kills 30% to 80% of people in the advanced stages of cancer.
"This exciting new [work] … offers potential answers to some of the great unsolved biomedical questions of our times," writes endocrinologist Matthias Tschöp, research director of the Helmholtz Diabetes Center near Munich, Germany, in an e-mail.
Brown fat is typically considered good because it burns calories, which may help people shed pounds. White fat, in contrast, accumulates in unhealthy locales like the waistline and buttocks, promoting obesity, diabetes, and heart disease.
But the tables are turned in people who suffer from the wasting syndrome cachexia, which develops in about half of all cancer patients as well as in the end stages of infectious diseases like AIDS and in chronic conditions like congestive heart failure. Scientists don’t know what causes cachexia, but it has been linked to higher metabolism in brown fat. The body burns off energy despite high-protein nutritional supplements and lack of exercise, and there is no effective treatment. The condition is often what disqualifies cancer patients from further treatment or clinical trials, says Michele Petruzzelli, a cancer biologist at the Spanish National Cancer Research Centre (CNIO) in Madrid.
White fat can turn into brown fat, and animal studies have found that one stimulus for this so-called browning is prolonged cold exposure, but researchers don’t know how browning occurs. “The same type of fat cell conversion that is good in heart disease and diabetes is bad in cancer,” Petruzzelli says.
Although many labs search for therapies against diseases of obesity by looking for ways to activate browning, Petruzzelli and colleagues viewed the same process as a potential villain in cancer patients. By analyzing metabolic pathways in numerous mouse models of cancer and in human cancer samples transplanted into mice, the team found that the browning of white fat “was consistent in all of these models and led irreversibly to cachexia,” says study co-author Erwin Wagner, a cancer biologist at CNIO. “This process is likely happening in these patients. It is using energy available in the body to instead kill the body, killing the patient.”
In the mouse models, the researchers were able to link the process to the systemic inflammation that’s often seen in cancer patients. They implicated interleukin-6 (IL-6), a cell signaling protein involved in stimulating the body’s immune response to inflammation. They then showed that anti-inflammatory drugs may prevent the white fat browning that precedes cancer cachexia and the wasting syndrome itself, the team reports online this week in Cell Metabolism.
Bruce Spiegelman, a cell biologist at the Dana-Farber Cancer Institute in Boston, recently reached a very similar conclusion in his own lab and published the result in Nature. Both papers, he says, “end any question that activation of fat browning is definitely part of cancer cachexia, at least in terms of animal models, and are pretty suggestive in people with cancer.”
Spiegelman’s lab used a different mouse model of cancer cachexia and searched for genetic changes in tumor cell function, homing in on a distinct molecular factor, tumor-derived parathyroid-hormone-related protein (PTHrP). When his group neutralized this protein in mice, “muscle wasting and cachexia were alleviated but not stopped,” Spiegelman says. He says that means other factors are likely involved, possibly IL-6.
Both studies suggest there may be possible treatments for cachexia, as well as better ways to diagnose it. Indeed, Wagner’s group found that browning begins very early, before muscle atrophy is observed, but that it may be detectable by imaging or biomarkers.
“Up to now, there has been no use for inhibitors of brown fat,” Petruzzelli says. “This could be a different approach to tackling cancer as a disease,” Wagner says, “because chemotherapies can make you weaker … but we want to strengthen the body’s response by preventing cachexia.”
The researchers say that comparatively nontoxic treatments like nonsteroidal anti-inflammatory drugs or specifically designed antibodies could change the way cancer is treated and benefit vast numbers of people who die from cachexia due to heart failure, HIV/AIDS, and diseases of aging.