Ablation of RAGE (receptor for advanced glycation end-products) translates into reduced tumorigenic and cachectic potential in LLC-tumor bearing mice

Cachexia is a highly debilitating multifactorial syndrome affecting advanced cancer patients, and characterized by body weight loss and skeletal muscle atrophy [1]. We reported that genetic ablation of RAGE (receptor for advanced glycation end-products) in mice translated into delayed loss of muscle mass and strength, reduced tumor progression, and increased survival, suggesting a major role of RAGE in the cachectic syndrome [2]. To elucidate the role of RAGE in the tumor environment promoting cachexia, we generated LLC (Lewis lung carcinoma) clones stably transfected with expression vectors for RAGEΔcyto (non-transducing RAGE), full-length RAGE or empty vector. We found that LLC/RAGEΔcyto cells showed reduced migration in in vitro assay and almost inability to form colonies in soft agar. When injected s.c. in WT and Ager-/- (RAGE-KO) mice, LLC/RAGEΔcyto cells formed smaller masses than LLC/RAGE cells, with the smallest and biggest tumor masses found in Ager-/- mice injected with LLC/RAGEΔcyto cells and in WT mice injected with LLC/RAGE cells, respectively. Tumor masses from Ager-/- mice showed reduced amounts of myeloid-derived suppressor cells (MDSCs), which promote cancer progression and cachexia [3]. In line, i) the expression of the atrogene Fbxo32 was found at the lowest levels in tibialis anterior muscles of Ager-/- mice injected with LLC clones, especially LLC/RAGEΔcyto; ii) LLC/RAGEΔcyto- conditioned medium was unable to induce C2C12 myotube atrophy in vitro. Our data suggest a critical role of RAGE expressed by LLC cells, in addition to RAGE expressed by the host animal, in sustaining tumor progression and cancer cachexia. Molecular targeting of RAGE emerges further as a promising approach to counteract muscle wasting in cancer patients. 1. Schmidt SF et al., Trends Cancer 2018;4(12):849-60. 2. Chiappalupi S et al. J Cachexia Sarcopenia Muscle 2020;11(4):929-46. 3. Gabrilovich DI et al., Nat Rev Immunol 2012;12(4):253-68.