March 29, 2016
Preliminary findings for two studies about the relationship of obesity and cancer, conducted in the laboratory of Stephen Hursting, PhD, will be presented April 18 and 19 at the 2016 American Association of Cancer Research annual meeting in New Orleans.
Hursting is professor of nutrition at the UNC Gillings School of Global Public Health and at the UNC Nutrition Research Institute in Kannapolis, N.C., and is a member of UNC Lineberger Comprehensive Cancer Center.
One study, first-authored by Emily Rossi, a predoctoral trainee at UNC Lineberger’s Cancer Control and Education Program, found that weight loss surgery was more effective than a low-fat diet at reversing the cancer-promoting effects of chronic obesity.
“Our basic finding was that surgical weight loss in obese mice was able to inhibit mammary tumor growth in a mouse model of basal-like breast cancer, while weight loss induced by a low-fat, low-calorie diet was not,” said Rossi.
She and her colleagues in Hursting’s lab are leading research aimed at understanding and potentially breaking the link between obesity and cancer.
“Data from human studies has suggested that there is something mechanistically different about bariatric surgery, relative to diet-induced weight loss, that makes the surgery more effective at preventing or controlling breast cancer,” Hursting said. “Now that we have (for the first time) replicated this surgery versus diet effect in an experimental model of breast cancer, we have the opportunity to determine the molecular and metabolic factors that are responsible for the protective effects of the surgery.”
Obesity is a significant risk factor for several types of breast cancer, including the basal-like breast cancer subtype. Rossi, Hursting and their colleagues have shown in previous research that obesity reversal through diet may not be enough to reverse the effects of chronic obesity on molecular drivers of cancer, including epigenetics and inflammation.
In the most recent preclinical study, mice were either fed a low-fat diet or an obesity-promoting high-fat diet for 15 weeks. Obese mice were then randomized to a weight loss surgical procedure called a sleeve gastrectomy, in which the surgeon removes a large portion of the stomach, or to lose the same amount of weight through a low-fat diet.
Rossi and colleagues found that tumor growth in obese mice that had the weight loss surgery was statistically equivalent to mice that had maintained a normal weight, but obese mice that lost weight through a low-fat diet had less anti-cancer benefit. Tumor growth in the mice that lost weight by diet mirrored the tumor growth seen in obese mice.
Surgical weight loss was also linked to lower levels of certain molecular drivers of cancer. Mice that went through surgical weight loss had lower levels of insulin and inflammatory proteins, suggesting that the surgery reduced obesity-linked increases in insulin, inflammation and breast cancer growth.
“One consequence of the obesity epidemic in the United States and many other countries is increasing rates of obesity-related cancer,” Hursting said. “However, we are not going to solve this growing problem through bariatric surgery, which, despite being effective, is too expensive and too difficult to be done on everyone who is obese. Our goal is to understand what the surgery is doing metabolically to slow tumors, and replicate those protective effects through combinations of diet, exercise and possibly drugs that target some of the same pathways as the bariatric surgery.”
In the second study, led by Laura Bowers, PhD, postdoctoral fellow at UNC Lineberger, researchers examined whether weight loss via four different diets was linked to reduced tumor growth in laboratory models of breast cancer. While tumor size did not differ between obese mice and obese mice that returned to a normal weight on a low-fat diet, they did find that obese mice that lost significant amounts of weight on three calorie-restricted diets had smaller tumors.
“Based on our results, it appears that the degree of calorie restriction, and hence the amount of weight lost, matters more than the specific dietary changes used to generate the weight loss,” said Bowers. “Our findings are too preliminary to make any kind of recommendation for people. The overall message is that the breast cancer-promoting effects of chronic obesity may not be easily reversible with moderate weight loss, but more severe weight loss diets may be effective regardless of whether carbohydrate or fat is restricted.”
Hursting said the findings were of increasing importance as the obesity epidemic in the United States and throughout the world is increasing the prevalence of obesity-related cancers.
“Obesity also makes cancers more deadly,” Hursting said. “We are working to identify mechanism-based interventions in our experimental models that can reverse the adverse effects of chronic obesity on cancer burden.”
In the study, researchers randomized mice to either maintain a normal weight or become obese by consuming a high-calorie diet for 15 weeks. Then, the obese mice were selected randomly to lose weight across 10 weeks on one of four diets: unrestricted consumption of a low-fat diet; a high-carbohydrate diet or low-carbohydrate diet, both with a 30 percent reduction in calories per day; or the increasingly popular “5:2” diet, involving intermittent reduction of calorie intake by 70 percent on two days per week.
Researchers found that mice on the low-fat diet returned to a normal weight and normal body fat percentage. Meanwhile, mice in the other three weight loss groups weighed significantly less after 10 weeks than mice that had maintained a normal body weight throughout the study.
The researchers then studied tumor growth. Mice in the obese group had greater tumor volume and weight compared to mice that maintained a normal weight throughout study. However, despite returning to a normal weight, tumor size in the mice on the low-fat diet was equivalent to the mice that remained obese. Mice on the three calorie-restricted diets had smaller tumors than both obese and low-fat diet mice.
Bowers said additional studies are needed to further clarify whether diet type is linked to tumor size. The impact of weight loss via the low-fat diet on tumor growth should be compared to other diets of the same calorie level that would produce equivalent weight loss. She also stated that the researchers currently are studying the molecular mechanisms that may be responsible for the differences in tumor size between diet groups.