Exercise, inflammation, and fatigue in cancer survivors

Abstract

Cancer-related fatigue significantly disrupts normal functioning and quality of life for a substantial portion of cancer survivors, and may persist for years following cancer treatment. While the causes of persistent fatigue among cancer survivors are not yet fully understood, accumulating evidence suggests that several pathways, including chronic inflammation, autonomic imbalance, HPA-axis dysfunction, and/or mitochondrial damage, could contribute towards the disruption of normal neuronal function and result in the symptom of cancer-related fatigue. Exercise training interventions have been shown to be some of the more successful treatment options to address cancer-related fatigue. In this review, we discuss the literature regarding the causes of persistent fatigue in cancer survivors and the mechanisms by which exercise may relieve this symptom. There is still much work to be done until the prescription of exercise becomes standard practice for cancer survivors. With improvements in the quality of studies, evidenced-based exercise interventions will allow exercise scientists and oncologists to work together to treat cancer-related fatigue.

Keywords: Cancer; Exercise; Fatigue; Inflammation; Physical Activity.

Figure 1

Systemic inflammation contributes to cancer-related fatigue. Cancer and its treatments activate leukocytes, resulting in increased expression of the transcription factor NF-κB and production of pro-inflammatory mediators, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ). Dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis leads to altered release of cortisol; glucocorticoid receptor (GCR) function on leukocytes is also decreased. Inflammation in the periphery leads to inflammation in the central nervous system (CNS) through several immune-to-brain communication pathways. Signals from sensory nerves activate CNS cells such as microglia to produce pro-inflammatory cytokines, including IL-6, TNF-α, and interlukin-1 beta (IL-1β). These inflammatory mediators then impact neurons directly or indirectly through altered oligodendrocyte, astrocyte, and endothelial cell functions. Inflammation in the periphery also decreases the availability of precursors, such as tetrahydrobiopterin (BH4) required for the synthesis of the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5HT). Deficits in serotonin production also occur as tryptophan (Trp) is converted into kynurenine from an inflammation-mediated increase in indoleamine 2,3-dioxygenase (IDO). Kynurenine is further metabolized in the brain into neurotoxic kynurenine metabolites such as 3-hydroxy kynurenine and quinolinic acid. Dashed lines indicate a disrupted pathway. CRH: corticotropin release hormone; ACTH: adrenocorticotropic hormone

Figure 2

Pathways by which exercise may ameliorate cancer-related fatigue. Exercise training confers psychological benefits, such as increased self-efficacy, and leads to improved fitness which eases the effort required for daily life activities. Exercise training decreases chronic inflammation through reductions in inflammatory cytokines, increased production of interleukin-10 (IL-10), and increased glucocorticoid receptor (GCR) function. Reduced inflammation in the periphery prevents disruption of neurotransmitter production (including norepinephrine (NE) and dopamine (DA)) and inflammation in the central nervous system (CNS). Exercise is further associated with increased neurotrophic factors such as brain derived neurotrophic factor (BDNF) and adiponectin. Exercise-induced increases in skeletal muscle PGC-1α expression, perhaps mediated by adiponectin, helps maintain levels of tryptophan (Trp) and serotonin (5HT) through activation of kynurenine aminotransferases (KATs), which favor the formation of neuroprotective kynurenine metabolites (kynurenic acid). PGC-1α may also promote mitochondrial biogenesis. Dashed lines indicate a disrupted pathway.