Receptor for advanced glycation end-products (RAGE) as a biomarker of muscle wasting in cancer conditions

Cachexia is a debilitating syndrome affecting the majority of patients with advanced cancer, and directly responsible for about 20% of all cancer-associated deaths. The major clinical feature of cachexia is skeletal muscle atrophy that leads to pronounced weight loss, drastically dampens patients’ quality of life, reduces the response and tolerance to chemotherapy, and is associated with poor prognosis and outcome (1). The identification of reliable biomarkers of cachexia is of great importance to identify patients in the different phases of the disease and to monitor the treatment outcome (2). RAGE (receptor for advanced glycation end-products) is a multiligand receptor of the immunoglobulin superfamily physiologically involved in skeletal muscle development and homeostasis (3). In cancer conditions, the increase of RAGE ligands levels leads to hyperstimulation of the receptor translating into systemic inflammation and muscle wasting, and reducing mouse survival (4). We analysed RAGE expression in muscle tissue of different preclinical mouse models of cancer cachexia [Lewis lung carcinoma (LLC)-bearing C57Bl/6 and colon adenocarcinoma (C26-ADK)-bearing BALB/c mice] in the absence or presence of voluntary endurance exercise (wheel), which has been reported to partially antagonize muscle wasting in mice (5), and correlated RAGE expression with myofiber cross-sectional area (CSA) and hallmarks of muscle atrophy (body and muscle weights, protein degradation extent, and activation of proteolytic systems). We also analysed RAGE expression in muscle biopsies from cancer patients. We found that: i) LLC- and C26-ADK-bearing mice express RAGE in myofibers in coincidence with reduced body and muscle weights and induction of proteolysis; ii) an inverse relationship exists between RAGE expression in muscles and tumor masses and the beneficial effects of endurance exercise in LLC-bearing mice; iii) RAGE expression increases in muscles during cachexia progression; iv) RAGE is not expressed in myofibers of athymic-nude mice injected subcutaneously with LLC or melanoma A375 cells, which do not develop cachexia; and v) muscles of cachectic patients express higher amounts of RAGE than non-cachectic subjects. Altogether, our results suggest that RAGE might represent a biomarker to monitor the cachectic stage at muscle level. 1) Porporato et al., Oncogenesis 2016, 5:e200; 2) Loumaye and Thissen, Clin Biochem 2017, 50:1281-8; 3) Riuzzi et al., J Cachexia Sarcopenia Muscle 2018, 9:1213-34; 4) Chiappalupi et al., J Cachexia Sarcopenia Muscle (under revision); 5) Aversa et al., Ther Adv Med Oncol 2017, 9:369-82.