Cancer Cachexia: More Than Skeletal Muscle Wasting

Cancer cachexia not only negatively affects the quality of life of patients but is also associated with a reduced efficacy and increased toxicity of chemotherapy, thereby contributing to mortality. Specific interventions preventing or reversing cachexia are anticipated to have an important positive impact on overall tumor disease outcome. Beyond the loss of skeletal muscle mass, cancer cachexia is now considered a systemic paraneoplastic phenomenon, affecting and comprising a variety of tissues. Intertissue communication has emerged as a critical component in the pathophysiology of cancer cachexia with important implications for future multimodal intervention strategies. Cancer cachexia is a multifactorial condition characterized by body weight loss that negatively affects quality of life and survival of patients with cancer. Despite the clinical relevance, there is currently no defined standard of care to effectively counteract cancer-associated progressive tissue wasting. Skeletal muscle atrophy represents the main manifestation of cancer cachexia. However, cancer cachexia is increasingly seen as a systemic phenomenon affecting and/or influenced by various organs. Here, we describe recent developments elucidating the roles of different tissues as well as tissue crosstalk in this wasting syndrome, including potential links to other cancer-associated morbidities. A more comprehensive understanding of cancer cachexia etiology and heterogeneity may enable the development of intervention strategies to prevent or reverse this devastating condition. Cancer cachexia is a multifactorial condition characterized by body weight loss that negatively affects quality of life and survival of patients with cancer. Despite the clinical relevance, there is currently no defined standard of care to effectively counteract cancer-associated progressive tissue wasting. Skeletal muscle atrophy represents the main manifestation of cancer cachexia. However, cancer cachexia is increasingly seen as a systemic phenomenon affecting and/or influenced by various organs. Here, we describe recent developments elucidating the roles of different tissues as well as tissue crosstalk in this wasting syndrome, including potential links to other cancer-associated morbidities. A more comprehensive understanding of cancer cachexia etiology and heterogeneity may enable the development of intervention strategies to prevent or reverse this devastating condition. a prominent systemic reaction of the organism to local or systemic disturbances in its homeostasis caused by infection, tissue injury, trauma, surgery, neoplastic growth, or immunological disorders. It represents an unspecific and acute inflammatory response comprising the synthesis of acute-phase proteins primarily by hepatocytes, which are released into the circulation. decreased sensation of appetite that can result in undernutrition. a process that allows regulated degradation and recycling of cellular components. In macroautophagy, targeted cytoplasmic constituents are transferred to double-membraned vesicles known as autophagosomes, which eventually fuse with lysosomes for degradation and recycling of the content. Three forms of autophagy are commonly described: macroautophagy, microautophagy, and chaperone-mediated autophagy. In the extreme case of energy deprivation, the breakdown of cellular components promotes cellular survival by maintaining cellular energy levels. possesses a number of specialized features enabling it to function as a thermoregulatory organ by generating heat. Brown adipocytes display a high density of mitochondria that are characterized by the unique presence of UCP1. the principal mechanism for protein catabolism in mammalian cells. The majority of intracellular proteins are degraded by the highly regulated UPP, which involves two successive steps: (i) tagging of the substrate protein by the covalent attachment of multiple ubiquitin molecules (conjugation); and (ii) subsequent degradation of the ubiquitinated protein by the 26S proteasome. located in the inner mitochondrial membrane where it mediates the translocation of protons into the mitochondrial matrix, thereby bypassing proton re-entry via the ATP synthase. Consequently, the energy of the proton gradient is dissipated as heat. The UCP1-mediated proton leak lowers the membrane potential, which increases electron flux through the respiratory chain, establishing a futile cycle able to produce considerable amounts of heat, thus increasing energy expenditure.