Exercise in People With Cancer: A Spotlight on Energy Regulation and Cachexia.

Exercise is increasingly becoming a standard of cancer care, with well-documented benefits for patients including improved mental wellbeing and reduced treatment-related side effects. However, important gaps in knowledge remain about how to optimise exercise prescription for people with cancer. Importantly, it remains unclear how exercise affects the progression of cancer cachexia (a wasting disease stemming from energy imbalance, and a common manifestation of advanced malignant disease), particularly once the condition has already developed. It was recently suggested that the anti-tumour effect of exercise might come from improved energetic capacity. Here, we highlight the possible effect of exercise on energetic capacity and energy regulation in the context of cancer, and how this might affect the progression of cancer cachexia. We suggest that due to the additional energy demand caused by the tumour and associated systemic inflammation, overreaching may occur more easily in people with cancer. Importantly, this could result in impaired anti-tumour immunity and/or the exacerbation of cancer cachexia. This highlights the importance of individualised exercise programs for people with cancer, with special consideration for the regulation of energy balance, ongoing monitoring and possible nutritional supplementation to support the increased energy demand caused by exercise.

Effect of immune modulation on the skeletal muscle mitochondrial exercise response: An exploratory study in mice with cancer.

Cancer causes mitochondrial alterations in skeletal muscle, which may progress to muscle wasting and, ultimately, to cancer cachexia. Understanding how exercise adaptations are altered by cancer and cancer treatment is important for the effective design of exercise interventions aimed at improving cancer outcomes. We conducted an exploratory study to investigate how tumor burden and cancer immunotherapy treatment (anti-PD-1) modify the skeletal muscle mitochondrial response to exercise training in mice with transplantable tumors (B16-F10 melanoma and EO771 breast cancer). Mice remained sedentary or were provided with running wheels for ~19 days immediately following tumor implant while receiving no treatment (Untreated), isotype control antibody (IgG2a) or anti-PD-1. Exercise and anti-PD-1 did not alter the growth rate of either tumor type, either alone or in combination therapy. Untreated mice with B16-F10 tumors showed increases in most measured markers of skeletal muscle mitochondrial content following exercise training, as did anti-PD-1-treated mice, suggesting increased mitochondrial content following exercise training in these groups. However, mice with B16-F10 tumors receiving the isotype control antibody did not exhibit increased skeletal muscle mitochondrial content following exercise. In untreated mice with EO771 tumors, only citrate synthase activity and complex IV activity were increased following exercise. In contrast, IgG2a and anti-PD-1-treated groups both showed robust increases in most measured markers following exercise. These results indicate that in mice with B16-F10 tumors, IgG2a administration prevents exercise adaptation of skeletal muscle mitochondria, but adaptation remains intact in mice receiving anti-PD-1. In mice with EO771 tumors, both IgG2a and anti-PD-1-treated mice show robust skeletal muscle mitochondrial exercise responses, while untreated mice do not. Taken together, we postulate that immune modulation may enhance skeletal muscle mitochondrial response to exercise in tumor-bearing mice, and suggest this as an exciting new avenue for future research in exercise oncology.

Effects of exercise and anti-PD-1 on the tumour microenvironment.

Immune checkpoint inhibition is highly effective in treating a subset of patients with certain cancers, such as malignant melanoma. However, a large proportion of patients will experience treatment resistance, and other tumour types, such as breast cancer, have thus far proven largely refractory to immune checkpoint inhibitors as single agents. Exercise has been associated with improved cancer patient survival, has known immune-modulatory effects, may improve anti-tumour immunity and may normalise tumour blood vessels. Therefore, we hypothesised that post-implant exercise would boost the effect of concurrent immunotherapy by enhancing anti-tumour immune responses and improving tumour blood flow. To investigate this, mice with EO771 breast tumours or B16-F10 melanomas received anti-PD-1, an isotype control antibody or no treatment. Mice were randomised to exercise (voluntary wheel running) or no exercise at tumour implant. Exercise reduced the number of CD8+T cells in EO771 (p = 0.0011) but not B16-F10 tumours (p = 0.312), and reduced the percentage of CD8+T cells within the total T cell population in both tumour types (B16-F10: p = 0.0389; EO771: p = 0.0015). In contrast, the combination of exercise and anti-PD-1 increased the percentage of CD8+T cells in EO771 (p = 0.0339) but not B16-F10 tumours. Taken together, our results show that exercise and anti-PD-1 induce changes in the tumour immune microenvironment which are dependant on tumour type.

Effect of post-implant exercise on tumour growth rate, perfusion and hypoxia in mice.

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.

Effects of Exercise on the Tumour Microenvironment.

Epidemiological evidence suggests that exercise improves survival in cancer patients. However, much is still unknown regarding the mechanisms of this positive survival effect and there are indications that exercise may not be universally beneficial for cancer patients. The key to understanding in which situations exercise is beneficial may lie in understanding its influence on the tumour microenvironment (TME)-and conversely, the influence of the tumour on physical functioning. The TME consists of a vast multitude of different cell types, mechanical and chemical stressors and humoral factors. The interplay of these different components greatly influences tumour cell characteristics and, subsequently, tumour growth rate and aggression. Exercise exerts whole-body physiological effects and can directly and indirectly affect the TME. In this chapter, we first discuss the possible role of exercise capacity ('fitness') and exercise adaptability on tumour responsiveness to exercise. We summarise how exercise affects aspects of the TME such as tumour perfusion, vascularity, hypoxia (reduced oxygenation) and immunity. Additionally, we discuss the role of myokines and other circulating factors in eliciting these changes in the TME. Finally, we highlight unanswered questions and key areas for future research in exercise oncology and the TME.

Characterisation of a Mouse Model of Breast Cancer with Metabolic Syndrome.

BACKGROUND/AIM: Patients with breast cancer and metabolic syndrome have poorer outcomes. We aimed to develop and characterise an apolipoprotein E-null/aromatase knockout (ApoE-/-/ArKO) mouse model of breast cancer with metabolic syndrome to aid research of the mechanisms behind poor prognosis. MATERIALS AND METHODS: Wild-type, ApoE-/- and ApoE-/-/ArKO mice were orthotopically implanted with EO771 murine breast cancer cells. Tumour growth was monitored and tumours investigated for pathological features such as cancer-associated adipocytes, hypoxia and cancer cell proliferation. RESULTS: Tumours from ApoE-/-/ArKO mice were significantly more proliferative than those from wild-type mice (p=0.003), and exhibited reduced expression of insulin-like growth factor binding protein-5 (p=0.002). However, ApoE-/-/ArKO mice also had a reduced rate of metastasis compared to wild-type and ApoE-/- mice. Tumour hypoxia and the number of cancer-associated adipocytes did not differ. CONCLUSION: The ApoE-/-/ArKO model with EO771 breast cancer provides a novel mouse model to investigate the effects of metabolic syndrome on aspects of breast tumour biology.

The Role of Exercise and Hyperlipidaemia in Breast Cancer Progression.

Exercise reduces the risk of breast cancer development and improves survival in breast cancer patients. However, the underlying mechanisms of this protective effect remain to be fully elucidated. It is unclear whether exercise can attenuate or modify the pro-tumour effects of obesity and related conditions, such as hyperlipidaemia. This review summarises how hyperlipidaemia and exercise contribute to or reduce breast cancer risk and progression, respectively, and highlights the possible mechanisms behind each. In particular, the effects of exercise and hyperlipidaemia on the immune microenvironment of tumours is analysed. The potential value of commonly investigated circulating factors as exercise-modulated, prognostic biomarkers is also discussed. We propose that exercise may alleviate some of the pro-tumorigenic effects of hyperlipidaemia through the reduction of blood lipid levels and modulation of cytokine release to induce beneficial changes in the tumour microenvironment.

Voluntary exercise slows breast tumor establishment and reduces tumor hypoxia in ApoE-/- mice.

Exercise reduces the risk of breast cancer development and improves survival in breast cancer patients. However, the underlying mechanisms of this protective effect remain to be fully elucidated, and it is unclear whether exercise can attenuate the protumor effects of obesity and related hyperlipidemia on breast cancer growth and development. We hypothesized that exercise attenuates the negative effect of hyperlipidemia through normalization of the tumor microenvironment and improved T cell infiltrate. Hyperlipidemic ApoE-/- mice with orthotopic EO771 breast tumors were randomly assigned to one of two voluntary running groups or sedentary controls, and muscular cytochrome c oxidase subunit IV (COX-IV) expression was used as a biomarker for the level of exercise. Tumors from mice with high muscular COX-IV expression took significantly longer to reach 100 mm3 ( P = 0.008), but showed no difference in growth rate once the tumor was established. Wheel running appeared to reduce internal metastases, but did not affect T cell infiltrate or the proportion of regulatory and cytotoxic T cells within the tumor. Serum levels of monocyte chemoattractant protein-1 (MCP-1) were significantly increased by tumor burden ( P = 0.02) and correlated with spleen weight ( P < 0.0001, R = 0.65). Furthermore, tumor hypoxia was significantly decreased in mice with high muscular COX-IV expression ( P = 0.01). Taken together, these results indicate that wheel running can slow the establishment of primary and secondary EO771 breast tumors and induce beneficial changes in the breast tumor microenvironment in ApoE-/- mice. NEW & NOTEWORTHY In this first study to investigate the effect of exercise on tumor behavior in a hyperlipidemic model, we hypothesized that wheel running would counteract the protumorigenic environment generated by hyperlipidemia. Wheel running slowed establishment of primary and secondary tumors and reduced tumor hypoxia but did not affect exponential tumor growth in ApoE-/- mice. Overall, voluntary wheel running induced favorable microenvironmental changes in breast tumors.