Systemic and local mechanisms leading to cachexia in cancer

Abstract

Cachexia is a multifactorial syndrome of atrophy of skeletal muscle and adipose tissue, resulting in progressive loss of body weight associated with low quality of life and poor prognosis in cancer. Studies on experimental animal models and observations on patients have shown that the soluble factors secreted by tumor cells and tissues of the patient can participate in regulation of the wasting process. Cachexia is often accompanied by anorexia, which is caused by predominance of signals inhibiting appetite in the hypothalamus, such as release of proopiomelanocortin and anorexigenic action of proinflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α). Cachexia is also accompanied by extensive metabolic changes consisting of increase of resting energy expenditure and disturbance of carbohydrate, protein and lipid metabolism. Increased expression of protein uncoupling phosphorylation leads to increased thermogenesis in skeletal muscle. Tumor tissue hypoxia caused by its growth beyond blood vessels activates the transcription factor HIF-1, which results in increase in glycolysis, and leads to lactic acid accumulation and activation of the energy inefficient Cori cycle. Loss of fat tissue is caused by increase of lipolysis induced by lipid-mobilizing factor (LMF) and proinflammatory cytokines. Skeletal muscle wasting in cachexia is caused by a reduction of protein synthesis at the stage of initiation and elongation of translation and the simultaneous increase of protein degradation via ubiquitin-dependent and lysosomal pathways. The main mediators of skeletal muscle wasting in cancer are proteolysis-inducing factor (PIF), proinflammatory cytokines, and angiotensin II acting through increased levels of reactive oxygen species (ROS) and nuclear factor NF-κB activation, as well as glucocorticoid activated FOXO transcription factors and myostatin. Understanding of the complexity of the interaction of factors produced by the tumor and the patient's body may form the basis for the development of effective treatments for cachexia in cancer and other pathological conditions.

Impact of physical exercise in cancer survivors during and after antineoplastic treatments

“…Gluconeogenesis is promoted by the high level of lactate derived from tumour glycolysis and is insensitive to physiological inhibitor stimuli such as the administration of glucose itself. Gluconeogenesis is an extremely energy-demanding process [ 45 ] and may be considered an important mechanism of the increased energy consumption in cancer patients. Gluconeogenesis also influences the protein metabolism, recruiting and therefore reducing amino acid levels.…”

“…A central alteration of the protein metabolism in cancer cachexia is the reduction of lean body mass. The depletion of lean mass is caused by an increase of muscular protein degradation without a correspondent increase of protein synthesis, which remains normal or is even slightly reduced [ 46 ]. There are three main mechanisms of muscle proteolysis: the lysosomal (cathepsin) proteolytic pathway, the calcium-activated system and the ubiquitin-proteasoma proteolytic pathway, which is the most important mechanism of protein degradation in cachexia [ 47 ].…”

Bu-Zhong-Yi-Qi pill alleviate the chemotherapy-related fatigue in 4 T1 murine breast cancer model

“…Saikosaponins are isolated as active ingredients of Radix Bupleuri, showed potent anti-inflammatory activities [ 47 ], anti-ulcerative [ 48 ], platelet activation inhibitory [ 49 ], corticosterone secretory [ 50 ], hepatoprotective [ 51 ], and nephroprotective [ 52 ] activities through their potent free radical scavenger effects, the antioxidant effects. Dehydroglyasperin D (DGD) is isolated from Glycyrrhizae also possessed the most potent antioxidant activity [ 53 ]. The present results suggested that BZYQ might effectively inhibited lipid peroxidation in muscle tissues, and acted directly or interacted with endogenous antioxidants for synergistic effects to defend against fatigue caused by PTX treated.…”

Feasibility single-arm study of a medical device containing <em>Desmodium adscendens</em> and <em>Lithothamnium calcareum</em> combined with chemotherapy in head and neck cancer patients

“… 6 Alterations in protein metabolism determine the increase in serum levels of protein-inducing factors and increased protein degradation in muscle tissue with loss of lean mass that is already evident at the early stages of the disease. 7 In addition, the production of lipid-metabolising factor induces consequent lipolysis that results in patients’ progressive weight loss. 8 Pro-inflammatory cytokines contribute to the pathophysiology of neoplastic cachexia, such as interleukins 1 and 6, tumor necrosis factor alpha, and interferon gamma, which in turn results in an increase in C-reactive protein (CRP), haptoglobin and ceruloplasmin that are responsible for increased fatty acid turnover and muscle proteolysis.…”