Modulation of Murine Breast Tumor Vascularity, Hypoxia, and Chemotherapeutic Response by Exercise

Abstract

Exercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor–negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11–12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm2, 95% CI = 1223 to 1865 vs 2168 cells/mm2, 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer.

Exercise-Dependent Regulation of NK Cells in Cancer Protection

“…Studies have shown that endurance training is associated with increased angiogenesis and vascularization in orthotropic mammary and prostate tumors from exercising mice and that such increased vascularization is correlated with enhanced blood perfusion and reduced tumor growth [72][73][74][75][76]. In addition to these long-term training studies in mice, McCullough et al have shown that perfusion of orthotropic prostate tumors increases immediately during treadmill running in tumor-bearing rats (as evidenced by in vivo injection of Hoechst-33342 stained tumor cells prior to animal culling) [74].…”

Modulation of the tumor vasculature and oxygenation to improve therapy

“…Importantly the increase in tumor blood flow resulted in a significant reduction in tumor hypoxia (Figure 10). The ability to modulate tumor hypoxia by exploiting the systemic effects of exercise and the dysfunctional vasculature of solid tumors have recently been duplicated in rodent mammary tumor models grown in the mammary fat pads (Betof et al, 2015; Lee et al, 2015). …”

Proceedings of the 5th annual symposium of the German Society for Paleo Nutrition held in 2017

“…Secondly, exercise has proven to mobilize and activate immune cells which are involved in the host-tumor defense, such as natural killer cells and cytotoxic T-cells [26,27]. Thirdly, it was speculated that exercise influences intratumoral angiogenesis [28]. Research of the past decade suggests, that some of the mentioned effects of PA are driven by exercise-induced epigenetic modifications [29,30].…”