A Narrative Review of Cancer-Related Fatigue (CRF) and Its Possible Pathogenesis

Abstract

Many cancer patients suffer from severe fatigue when treated with chemotherapy or radiotherapy; however, the etiology and pathogenesis of this kind of fatigue remains unknown. Fatigue is associated with cancer itself, as well as adjuvant therapies and can persist for a long time. Cancer patients present a high degree of fatigue, which dramatically affects the quality of their everyday life. There are various clinical research studies and reviews that aimed to explore the mechanisms of cancer-related fatigue (CRF). However, there are certain limitations in these studies: For example, some studies have only blood biochemical texts without histopathological examination, and there has been insufficient systemic evaluation of the dynamic changes in relevant indexes. Thus, we present this narrative review to summarize previous studies on CRF and explore promising research directions. Plenty of evidence suggests a possible association between CRF and physiological dysfunction, including skeletal muscular and mitochondrial dysfunction, peripheral immune activation and inflammation dysfunction, as well as central nervous system (CNS) disorder. Mitochondrial DNA (mtDNA), mitochondrial structure, oxidative pressure, and some active factors such as ATP play significant roles that lead to the induction of CRF. Meanwhile, several pro-inflammatory and anti-inflammatory cytokines in the peripheral system, even in the CNS, significantly contribute to the occurrence of CRF. Moreover, CNS function disorders, such as neuropeptide, neurotransmitter, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction, tend to amplify the sense of fatigue in cancer patients through various signaling pathways. There have been few accurate animal models established to further explore the molecular mechanisms of CRF due to different types of cancer, adjuvant therapy schedules, living environments, and physical status. It is imperative to develop appropriate animal models that can mimic human CRF and to explore additional mechanisms using histopathological and biochemical methods. Therefore, the main purpose of this review is to analyze the possible pathogenesis of CRF and recommend future research that will clarify CRF pathogenesis and facilitate the formulation of new treatment options.

Keywords: cancer-related fatigue; central nervous system; inflammatory cytokines; mitochondrion; peripheral immune activation; skeletal muscle.

Figure 1

Cancer-related fatigue (CRF) is associated with various risk factors. The predominant factors are demographic characteristics, pathological factors, the types of cancer, and anti-cancer treatment schedules.

Figure 2

When treated with chemotherapy or radiotherapy, the regular structure and function of mitochondria are damaged through different signaling pathways. The processes involved in the transcription of nDNA and mtDNA are significantly destroyed, and the levels of mtROS and mtRNS are upregulated when skeletal muscle is nonspecifically targeted by chemotherapies. Meanwhile, the respiratory function of mitochondria is weakened by the impaired mitochondrial membrane. The Cu²⁺ capacity is critical for mitochondrial complexes and ATP generation, so when Cu²⁺ is competitively inhibited by some chemotherapies, such as oxaliplatin, the outflow of Cu²⁺ increases, which is harmful to the mitochondrial energy generation. In general, direct chemo/radio-therapy injuries, hyperoxidative stress, and a low energy supply are likely to cause physical fatigue via apoptosis or other detrimental signaling pathways.

Figure 3

Inflammatory cytokines such as TNF-α, IL-1β, IL-2, IL-6, and INF-γ, which are correlated with the severity of fatigue, play a significant role in peripheral immune activation. Cytokines are primarily generated by immune cells and regulate inflammatory responses through peripheral, neural, and even systematic circulations. The pro/anti-inflammatory function encourages the body to maintain relative homeostasis by autocrine and paracrine communication between immune cells. When stimulated by chemotherapies, the inflammatory responses of immune cells are further strengthened, and the secretion of cytokines such as NF-κB, IL-1β, and TNF-α into the peripheral or neural circulation is increased. These changes lead to more severe fatigue symptoms that are closely linked to the incidence of CRF.

Figure 4

The central nervous system (CNS) integrates the signals from peripheral circulations to inhibit or amplify immune signals through neural regulation mechanisms. On the account of inflammatory stress, peripheral inflammatory cytokines enter the brain through various routes to activate microglia and astrocytes and to generate neurotoxins that cause neuroinflammation in the CNS. Furthermore, inflammation of the nervous system leads to severe disorders of systemic circulations, such as decreased blood-brain barrier (BBB) strength, atrophy of spinal gray matter, or decreased muscular innervation. A nervous system affected by peripheral or central inflammatory responses is inclined to destroy muscle cells and inhibit the generation of energy and nutrition, leading to motor unit decrease and severe fatigue, both physical and mental.