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Background: Intratumoral hypoxia (pO2 <10mmHg) is associated with aggressive tumor progression and poor patient outcome. It is often found in solid tumors, and can constitute a major obstacle to anticancer therapy. The primary cause of abnormal oxygen tensions in tumors is the aberrant tumor vasculature, characterized by tortuous, leaky and immature vessels. A number of intervention strategies designed to overcome tumor hypoxia have been investigated including high oxygen content breathing and the use of bioreductive prodrugs, but these have had only moderate success in the clinic.
Purpose: The goal of the present investigations was to determine whether aerobic exercise could be applied as a means to improve tumor physiology and decrease tumor hypoxia in breast cancer models.
Methods: The effects of single and repeated bouts of moderate intensity exercise (treadmill running) were studied in mice bearing syngeneic murine mammary carcinoma models (EMT6 and 4T1). The exercise intensities were determined by measuring the anaerobic threshold, which is reflected by the steady rise in blood lactate during an exercise bout. Mice were orthotopically injected with tumor cells and once the tumors reached a size of 250 mm3, the mice were exposed to either a single bout of exercise or daily exercise bouts performed for 5 consecutive days. Controls for each treatment consisted of sedentary mice exposed to a stationary treadmill for the equivalent amount of time. Following cessation of each exercise regime tumors were harvested, sectioned and evaluated by immunofluorescence. Vessel density (MECA-32), blood perfusion (Hoechst-33342) and hypoxia (EF5) were quantified and significance was established at p<0.05.
Results: Preliminary data indicate that even a single exercise bout may begin to demonstrate improvements in blood vessel perfusion and tumor oxygenation. Importantly, after 5 daily bouts of exercise, there was a significant increase in the number of patent vessels and improvement in oxygenation in the tumors of exercising mice compared to those of sedentary controls.
Conclusion: The results indicate that moderate aerobic exercise can improve the oxygenation status of solid tumors. These findings suggest that such a non-toxic intervention may have potential utility in overcoming hypoxia-associated treatment resistance in cancer patients and improve patient outcome.