Abstract
Preclinical studies have shown a larger inhibition of tumour growth when exercise begins prior to tumour implant (preventative setting) than when training begins after tumour implant (therapeutic setting). However, post-implantation exercise may alter the tumour microenvironment to make it more vulnerable to treatment by increasing tumour perfusion while reducing hypoxia. This has been shown most convincingly in breast and prostate cancer models to date and it is unclear whether other tumour types respond in a similar way. We aimed to determine whether tumour perfusion and hypoxia are altered with exercise in a melanoma model, and compared this with a breast cancer model. We hypothesised that post-implantation exercise would reduce tumour hypoxia and increase perfusion in these two models. Female, 6-10 week old C57BL/6 mice were inoculated with EO771 breast or B16-F10 melanoma tumour cells before randomisation to either exercise or non-exercising control. Exercising mice received a running wheel with a revolution counter. Mice were euthanised when tumours reached maximum ethical size and the tumours assessed for perfusion, hypoxia, blood vessel density and proliferation. We saw an increase in heart to body weight ratio in exercising compared with non-exercising mice (p = 0.0008), indicating that physiological changes occurred with this form of physical activity. However, exercise did not affect vascularity, perfusion, hypoxia or tumour growth rate in either tumour type. In addition, EO771 tumours had a more aggressive phenotype than B16-F10 tumours, as inferred from a higher rate of proliferation (p<0.0001), a higher level of tumour hypoxia (p = 0.0063) and a higher number of CD31+ vessels (p = 0.0005). Our results show that although a physiological training effect was seen with exercise, it did not affect tumour hypoxia, perfusion or growth rate. We suggest that exercise monotherapy is minimally effective and that future preclinical work should focus on the combination of exercise with standard cancer therapies.
Highlights
It is well-established that exercise or physical activity is efficacious in a number of different ways at different time-points along the cancer continuum
We saw no difference in tumour growth rate between mice with or without access to a running wheel for both B16-F10 and EO771 tumours (Fig 1C and 1D, S1 Fig), and there was no difference in survival (Fig 1A and 1B)
We found that hypoxic area and perfused vessel number were unchanged in tumours from exercising compared with non-exercising mice, for both B16-F10 and EO771 tumours (Fig 3A–3E)
Summary
It is well-established that exercise or physical activity is efficacious in a number of different ways at different time-points along the cancer continuum. Pre-diagnosis physical activity reduces the risk of developing a range of different cancers, including breast cancer [1]. In terms of survival outcomes, post-diagnosis exercise reduces breast cancer mortality by approximately 40% (systematically reviewed in [3]). The authors found that pre-diagnosis exercise did not affect survival outcomes in patients with high-risk primary melanoma [4]. Survival rates for primary melanoma are very high regardless (>90%, [5]), which means there is little room for improvement. It is unknown whether post-diagnosis exercise affects survival outcomes in either primary or metastatic melanoma patients
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