Toward the identification of receptor for advanced glycation end-products (RAGE) as a muscle biomarker of cancer cachexia.

Introduction: Cachexia is a debilitating syndrome affecting more than 50% of patients with advanced cancer. Its major clinical feature is skeletal muscle atrophy leading to pronounced weight loss, reduced quality of life, and poor prognosis. The identification of valuable biomarkers of early cachexia is of great importance to identify the patients at risk of cachexia and to treat patients in the reversible phase of the disease (Porporato et al., Oncogenesis 2016, Loumaye- Thissen, Clin Biochem 2017). RAGE (receptor for advanced glycation end-products) signalling concurs to skeletal muscle development and homeostasis (Riuzzi et al., JCSM 2018); however, in cancer conditions, RAGE hyperstimulated by high levels of its ligands leads to muscle wasting, sustains inflammation, and reduces survival of mice (Chiappalipi et al., submitted). Here, we investigated whether RAGE might represent a biomarker of cachexia. Methods: We analysed RAGE expression in muscle tissue of different tumour-bearing mice in the absence or presence of endurance exercise and correlated it with myofiber CSA and hallmarks of atrophy (body and muscle weights, protein degradation, and activation of the proteolytic systems). We performed RAGE expression analysis in muscle biopsies of cancer patients. Results: We found that (i) Lewis lung carcinoma (LLC)-bearing C57Bl/6 mice and colon adenocarcinoma (C26-ADK)-bearing BALB/c mice express RAGE in myofibres in coincidence with reduced body and muscle weight and induction of proteolysis; (ii) an inverse relationship exists between RAGE expression in muscles, tumour masses, and the beneficial effects of endurance exercise in LLC-bearing mice; (iii) RAGE expression increases in muscles during cachexia progression; (iv) LLC or melanoma A375 cells injected in athymic-nude mice are not able to induce neither cachexia nor RAGE expression in muscle; and (v) muscles of cachectic patients express higher amounts of RAGE than non-cachectic subjects. Conclusions: RAGE might represent a muscle biomarker of the cachectic stage.