Fig. 1
Simplified, hypothetical mechanism(s) whereby exercise may modulate aspects of the TME and potential antioxidant / pro-oxidant responses. Exercise stimulates numerous responses that influence the systemic milieu and may modify components of the TME. Naturally, the onset of exercise immediately promotes a cardiorespiratory response, potentially enhancing tumour perfusion and O2 delivery. Within skeletal muscle, enhanced metabolic demand and the generation of ROS activate several intracellular signalling pathways and key transcriptional factors, culminating in the expression of genes encoding antioxidant enzymes and myokines (and potentially other relevant factors). Theoretically, exercise-induced reactive derivatives and/or the subsequent expression of myokines into circulation (dashed arrows), may influence the systemic milieu and hypoxic signalling, driving anti-proliferative, antioxidant signalling intrinsically. Alternatively, vigorous exercise alongside radiotherapy could conceivably create sufficiently high (toxic) concentrations within the TME, inducing apoptosis (both potential theories marked with a question mark as presently unknown). The potential role of H2O2 remains poorly understood (unknown signalling properties and membrane permeability in this model marked with a question mark), though it may serve as an important signalling factor. Abbreviations AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; DNA, deoxyribonucleic acid; H2O2, hydrogen peroxide; MAPK, mitogen-activated protein kinase; Mod, moderate; NAD, nicotinamide adenine dinucleotide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; O2, oxygen; O2•−, superoxide; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, superoxide dismutase; TME, tumour microenvironment