Caloric Restriction Reduces Mammary Tumor Growth and Metastases

Abstract

Caloric restriction (CR) is the most widely studied model of extending lifespan. Several studies have demonstrated that CR has beneficial effects on limiting tumor growth; however, less is known about CR effects on metastases and the extracellular matrix (ECM), which is important for tumor invasiveness. We investigated this in a mouse breast cancer model (4T1). Mice were fed with normal diet (ND) or 40% CR. After 5 weeks on diets, 4T1 cells were injected into BALB/c mice and diets continued for the remainder of the experiment. Mice under CR had a 23% reduction in body weight compared to ND mice (p<0.01). CR reduced tumor growth and weight (CR: 1.5±0.3 vs. ND: 3.5±0.4g; p<0.01). Tumors from CR mice demonstrated a 64% decreasein the cell proliferative index (p<0.01), lower microvessel density (p<0.05) and total vessel length (p<0.01) and increased apoptosis (p<0.05). CR reduced (p<0.05) the numbers and sizes of spontaneous and experimental (p<0.05) lung metastases. CR mice demonstrated lower MMP‐9 (matrix metalloproteinase‐9) activity (ND: 1.1±0.1 and CR: 0.7±0.1 ng/ug protein; p<0.05) and a 34% lower total collagen intra‐tumor volume fraction compared to ND mice, p<0.05. Our results suggest that CR reduces mammary tumor growth and its metastases, by increasing apoptosis, reducing proliferation and angiogenesis, while remodeling the ECM.