Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model

Abstract

Regular physical exercise is considered to be an integral component of cancer care strategies. However, the effect of exercise training on tumor microvascular oxygenation, hypoxia, and vascular function, all of which can affect the tumor microenvironment, remains unknown. Using an orthotopic preclinical model of prostate cancer, we tested the hypotheses that, after exercise training, in the tumor, there would be an enhanced microvascular Po₂, increased number of patent vessels, and reduced hypoxia. We also investigated tumor resistance artery contractile properties. Dunning R-3327 AT-1 tumor cells (10⁴) were injected into the ventral prostate of 4–5-mo-old male Copenhagen or Nude rats, which were randomly assigned to tumor-bearing exercise trained (TB-Ex trained; n = 15; treadmill exercise for 5–7 wk) or sedentary groups (TB-Sedentary; n = 12). Phosphorescence quenching was used to measure tumor microvascular Po₂, and Hoechst-33342 and EF-5 were used to measure patent vessels and tumor hypoxia, respectively. Tumor resistance artery function was assessed in vitro using the isolated microvessel technique. Compared with sedentary counterparts, tumor microvascular Po₂ increased ∼100% after exercise training (TB-Sedentary, 6.0 ± 0.3 vs. TB-Ex Trained, 12.2 ± 1.0 mmHg, P < 0.05). Exercise training did not affect the number of patent vessels but did significantly reduce tumor hypoxia in the conscious, resting condition from 39 ± 12% of the tumor area in TB-Sedentary to 4 ± 1% in TB-Ex Trained. Exercise training did not affect vessel contractile function. These results demonstrate that after exercise training, there is a large increase in the driving force of O₂ from the tumor microcirculation, which likely contributes to the considerable reduction in tumor hypoxia. These results suggest that exercise training can modulate the microenvironment of the tumor, such that a sustained reduction in tumor hypoxia occurs, which may lead to a less aggressive phenotype and improve patient prognosis.