Effect of Moderate and High Intensity Exercise on Hypoxia and Radiosensitivity in Tumor‐Bearing Rats

Abstract

Background Prostate tumors typically have hypoxic regions that are resistant to traditional radiation therapy. Prior evidence from our laboratory has demonstrated improved perfusion and reduced hypoxia of prostate tumors with moderate intensity exercise training; such changes have potential to enhance radiation therapy. However, there is a dearth of evidence for the magnitude of alterations of intra-tumor hypoxia markers with exercise, as well as the ideal intensity of exercise for combating hypoxia in solid tumors. Using a pre-clinical orthotopic model of prostate cancer, we tested the hypothesis that exercise training at both moderate and high intensities would result in a decrease in hypoxia assessed via immunohistochemical analysis of hypoxic markers. Further, that enhanced radiotherapy responses would occur in exercise trained tumor bearing animals compared to sedentary counterparts. Methods Immunocompetent male Copenhagen rats aged 6 months (n=48) were injected orthotopically (ventral lobe of prostate) with 1x105 Dunning R-3327 AT-1 prostate adenocarcinoma cells. All animals were first acclimated to treadmill exercise and randomized into three groups: tumor bearing sedentary (TBS, n=20), moderate intensity training, (TBMIT, n=12), or high intensity training (TBHIT, n=16). After 7 days of recovery from surgery, both exercise groups began progressive exercise training on a motorized treadmill at either 20/min with a 5% incline, or 30m/min 15% incline for 10 minutes a day progressing to 60 min/day for TBMIT and TBHIT, respectively, for approximately 5 weeks. Immunohistochemical analysis and whole-body ionizing radiation (2 Gy) were performed at the end of the 5-week period of training followed by clonogenic cell survival assay to assess survival fraction. Results There were no significant differences (p>0.05) in tumor mass between groups (TBS 7.8±1.1; TBMIT 7.2±1.3; TBHIT 6.4±0.9 g). Overall expression levels of hypoxia inducible factor 1-alpha (HIF-1a, n=40) were significantly greater in the TBS group vs both the TBMIT and TBHIT (TBS 37.9±7.4; TBMIT 25.5±6.1; TBHIT 14.4±5.7%, p<0.05), with a trend for increased expression in TBMIT vs TBHIT (p=0.059). The survival fraction (n=8) was also significantly higher in TBS when compared to both TBMIT and TBHIT (TBS 39.9±5.3; TBMIT 23.2±3.2; TBHIT 20.7±4.9%, p<0.05). Conclusion This study suggests that compared to sedentary counterparts, both chronic moderate and high intensity exercise training modify the tumor microenvironment (decreased levels of HIF-1a) favorably. Given exercise therapy is becoming increasingly recommended to mitigate fatigue and increase quality of life in patients, a potential therapeutic component could add to the efficacy of exercise prescription in a clinical setting.