Molecular mechanisms of cancer cachexia‐related loss of skeletal muscle mass: data analysis from preclinical and clinical studies

Abstract

Cancer cachexia is a systemic hypoanabolic and catabolic syndrome that diminishes the quality of life of cancer patients, decreases the efficiency of therapeutic strategies and ultimately contributes to decrease their lifespan. The depletion of skeletal muscle compartment, which represents the primary site of protein loss during cancer cachexia, is of very poor prognostic in cancer patients. In this review, we provide an extensive and comparative analysis of the molecular mechanisms involved in the regulation of skeletal muscle mass in human cachectic cancer patients and in animal models of cancer cachexia. We summarize data from preclinical and clinical studies investigating how the protein turnover is regulated in cachectic skeletal muscle and question to what extent the transcriptional and translational capacities, as well as the proteolytic capacity (ubiquitin-proteasome system, autophagy-lysosome system and calpains) of skeletal muscle are involved in the cachectic syndrome in human and animals. We also wonder how regulatory mechanisms such as insulin/IGF1-AKT-mTOR pathway, endoplasmic reticulum stress and unfolded protein response, oxidative stress, inflammation (cytokines and downstream IL1ß/TNFα-NF-κB and IL6-JAK-STAT3 pathways), TGF-ß signalling pathways (myostatin/activin A-SMAD2/3 and BMP-SMAD1/5/8 pathways), as well as glucocorticoid signalling, modulate skeletal muscle proteostasis in cachectic cancer patients and animals. Finally, a brief description of the effects of various therapeutic strategies in preclinical models is also provided. Differences in the molecular and biochemical responses of skeletal muscle to cancer cachexia between human and animals (protein turnover rates, regulation of ubiquitin-proteasome system and myostatin/activin A-SMAD2/3 signalling pathways) are highlighted and discussed. Identifying the various and intertwined mechanisms that are deregulated during cancer cachexia and understanding why they are decontrolled will provide therapeutic targets for the treatment of skeletal muscle wasting in cancer patients.

Amino acids and cancer: potential for therapies?

“…Another parallel and dependent mechanism to this condition is that physiologically, the hypothalamus is responsible for controlling food intake and energy expenditure. In summary, with the activation of the inflammatory condition triggered by cytokines, the body develops adeptly by suppressing appetite by inverting the secretion of neuropeptides (activating anorexigenic and inhibiting orexigenic) [5].…”

“…Poor food intake and consequent nutritional loss often occur in cancer patients, thus leading to negative clinical results. Therefore, nutritional therapy, especially when performed early, is part of the support for these patients, whose objective is to maintain quality of life and greater tolerance to cancer treatment [4 ▪▪ ,5,9,10,11 ▪▪ ].…”

“…Furthermore, it is unclear whether a diet rich in proteins or specific amino acids is beneficial for preserving and recovering muscle mass or for increasing the immune response in cancer patients. Still, it is not clear what the protein recommendation is in relation to the different phases of oncological treatment and what would be the ideal period of this recommendation to favor clinically positive results [3,5,9,10,11 ▪▪ ].…”

“…Therefore, this review aims to describe and highlight studies focusing on current evidence in view of protein and amino acid recommendations, in addition to outlining the action of these nutrients in the metabolism of cancer patients. system cells are determinants for the development of symptoms of cancer [5]. Enhanced inflammatory responses intervened by pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-a), increase the expression of muscle atrophy-specific protein ligases (E3), including atrogin-1/MAFbx and muscle ring finger-1 (MURF-1) impairing the molecular pathways of muscle protein synthesis [6,7].…”

“…The result of hypercatabolism caused by intense inflammatory activity associated with decreased food intake can lead patients to insufficient protein-energy reserves, leading to malnutrition, sarcopenia, and cachexia [5]. In addition to these conditions, we still have several factors that present greater risks for developing the associated disorders mentioned above, such as advanced types of cancer, including head and neck, lung, gastrointestinal tract, liver, and pancreas; side effects of oncological treatments (chemotherapy, surgery, and radiotherapy) causing cytotoxic damage to tumor cells; and the presence of early satiety, changes in smell or taste, dysphagia, and odynophagia [3,5,8].…”