Overweight and obese individuals are at higher risk of cancer. Currently, with more than 2 in 3 adults considered to be overweight or obese in the U.S., understanding the mechanisms for this increased cancer risk is critical. One relatively unexplored mechanism that could link obesity with cancer risk is angiogenesis, a process where new blood vessels form from preexisting vessels allowing tissues to expand. In obesity, adipose tissue requires angiogenesis to form and expand, while in cancer, angiogenesis plays a role in tumor vascularization.
In the randomized controlled trial of 173 post-menopausal women, Physical Activity for Total Health trial, Drs. Catherine Duggan, Anne McTiernan and colleagues (Public Health Sciences Division) previously found that women who lost baseline fat mass in a year-long exercise intervention, experienced significant reductions in certain biomarkers of angiogenesis, compared to sedentary controls. As an extension of this work, the investigators sought to examine the independent and combined effects of dietary weight loss and exercise on circulating levels of angiogenic biomarkers in 439 participants enrolled in the Nutrition & Exercise for Women (NEW) study. These results were recently presented in Cancer Research.
The investigators randomly assigned 439 overweight/obese, healthy, postmenopausal women from the NEW trial to four arms: 1) caloric restriction diet arm (goal: 10% weight loss, N = 118), 2) aerobic exercise arm (225 minutes/week of moderate-to-vigorous activity, N = 117), 3) combined diet + exercise arm (N = 117), or 4) control arm (no intervention, N = 87). At baseline and 12 months of the study, the following angiogenic biomarkers were measured on all participants: plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor (serpin) that promotes angiogenesis; pigment epithelium-derived factor (PEDF), an adipokine and serpin with anti-angiogenic properties; and vascular endothelial growth factor (VEGF), a key regulator of angiogenesis and vascular permeability.
Using the generalized estimating equations to account for intra-individual correlation over time, investigators compared mean 12-month biomarker changes in the intervention arms to controls, while adjusting for baseline BMI, age, and race/ethnicity. They found that participants randomized to the diet and exercise arm had statistically significantly greater reductions in PAI-1 at 12 months compared with controls (-19.3% vs. +3.48%, respectively, P < 0.0001). Counterintuitively, participants randomized to the diet and diet + exercise arms had statistically significantly greater reductions in anti-angiogenic PEDF (-9.20%, -9.90%, respectively, P < 0.0001) compared with controls. Lastly, these diet and diet + exercise arms had greater reductions in VEGF (-8.25%, -9.98%, respectively, P ≤ 0.0005) than controls.
Interestingly, while increasing weight loss was associated with linear trends of greater reductions in PAI-1, PEDF, and VEGF, there were no differences in any of the biomarkers in participants randomized to the exercise arm compared with controls.
"These data confirm the importance of weight loss in reducing levels of circulating biomarkers associated with breast cancer risk", as Dr. Duggan reflects. "VEGF and PAI-1 are key components of the angiogenic process, involved in both tumor growth and in adipogenesis i.e., fat tissue growth and remodeling. Weight loss could thus improve the angiogenic profile’ of individuals, and may represent a potential method of reducing cancer risk." The next frontier of this research, according to Dr. Duggan, involves an epigenetic approach of examining "changes in gene expression of these angiogenic factors in muscle and adipose tissue in response to weight loss and exercise in similar populations."
Funding for this study was provided by the National Cancer Institute, the National Institutes of Health, and from the Breast Cancer Research Foundation.
Duggan C, Tapsoba JD, Wang CY, McTiernan A. 2016. Dietary Weight Loss and Exercise Effects on Serum Biomarkers of Angiogenesis in Overweight Postmenopausal Women A Randomized Controlled Trial. Cancer Research. Epub ahead of print.