{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T21:33:21Z","timestamp":1778362401162,"version":"3.51.4"},"reference-count":49,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T00:00:00Z","timestamp":1583884800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004486","name":"Fondazione Cassa di Risparmio di Perugia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004486","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2020,8]]},"abstract":"Abstract<\/jats:title>Background<\/jats:title>Cachexia, a multifactorial syndrome affecting more than 50% of patients with advanced cancer and responsible for ~20% of cancer\u2010associated deaths, is still a poorly understood process without a standard cure available. Skeletal muscle atrophy caused by systemic inflammation is a major clinical feature of cachexia, leading to weight loss, dampening patients' quality of life, and reducing patients' response to anticancer therapy. RAGE (receptor for advanced glycation end\u2010products) is a multiligand receptor of the immunoglobulin superfamily and a mediator of muscle regeneration, inflammation, and cancer.<\/jats:p><\/jats:sec>Methods<\/jats:title>By using murine models consisting in the injection of colon 26 murine adenocarcinoma\u00a0(C26\u2010ADK) or Lewis lung carcinoma (LLC) cells in BALB\/c and C57BL\/6 or Ager<\/jats:italic>\u2212\/\u2212<\/jats:sup> (RAGE\u2010null) mice, respectively, we investigated the involvement of RAGE signalling in the main features of cancer cachexia, including the inflammatory state. In vitro<\/jats:italic> experiments were performed using myotubes derived from C2C12 myoblasts or primary myoblasts isolated from C57BL\/6 wild type and Ager<\/jats:italic>\u2212\/\u2212<\/jats:sup> mice treated with the RAGE ligand, S100B (S100 calcium\u2010binding protein B), TNF (tumor necrosis factor)\u03b1\u00b1IFN (interferon) \u03b3, and tumour cell\u2010 or masses\u2010conditioned media to analyse hallmarks of muscle atrophy. Finally, muscles of wild type and Ager<\/jats:italic>\u2212\/\u2212<\/jats:sup> mice were injected with TNF\u03b1\/IFN\u03b3 or S100B in a tumour\u2010free environment.<\/jats:p><\/jats:sec>Results<\/jats:title>We demonstrate that RAGE is determinant to activate signalling pathways leading to muscle protein degradation in the presence of proinflammatory cytokines and\/or tumour\u2010derived cachexia\u2010inducing factors. We identify the RAGE ligand, S100B, as a novel factor able to induce muscle atrophy per se<\/jats:italic> via a p38 MAPK (p38 mitogen\u2010activated protein kinase)\/myogenin axis and STAT3 (signal transducer and activator of transcription 3)\u2010dependent MyoD (myoblast determination protein 1) degradation. Lastly, we found that in cancer conditions, an increase in serum levels of tumour\u2010derived S100B and HMGB1 (high mobility group box 1) occurs leading to chronic activation\/overexpression of RAGE, which induces hallmarks of cancer cachexia (i.e. muscle wasting, systemic inflammation, and release of tumour\u2010derived pro\u2010cachectic factors). Absence of RAGE in mice translates into reduced serum levels of cachexia\u2010inducing factors, delayed loss of muscle mass and strength, reduced tumour progression, and increased survival.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>RAGE is a molecular determinant in inducing the hallmarks of cancer cachexia, and molecular targeting of RAGE might represent a therapeutic strategy to prevent or counteract the cachectic syndrome.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12561","type":"journal-article","created":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T11:44:21Z","timestamp":1583927061000},"page":"929-946","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":100,"title":["Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8377-0665","authenticated-orcid":false,"given":"Sara","family":"Chiappalupi","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine University of Perugia Perugia Italy"},{"name":"Interuniversity Institute of Myology Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1973-9679","authenticated-orcid":false,"given":"Guglielmo","family":"Sorci","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Perugia Perugia Italy"},{"name":"Interuniversity Institute of Myology Perugia Italy"},{"name":"Centro Universitario di Ricerca sulla Genomica Funzionale University of Perugia Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8275-0099","authenticated-orcid":false,"given":"Aleksandra","family":"Vukasinovic","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Perugia Perugia Italy"},{"name":"Interuniversity Institute of Myology Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9409-2046","authenticated-orcid":false,"given":"Laura","family":"Salvadori","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Perugia Perugia Italy"},{"name":"Interuniversity Institute of Myology Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Sagheddu","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Perugia Perugia Italy"},{"name":"Interuniversity Institute of Myology Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7373-1953","authenticated-orcid":false,"given":"Dario","family":"Coletti","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic and Orthopedic Sciences Sapienza University of Rome Rome Italy"},{"name":"CNRS UMR 8256, INSERM ERL U1164, Biological Adaptation and Aging B2A Sorbonne Universit\u00e9 Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9762-6493","authenticated-orcid":false,"given":"Giorgia","family":"Renga","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Perugia Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1356-525X","authenticated-orcid":false,"given":"Luigina","family":"Romani","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Perugia Perugia Italy"},{"name":"Centro Universitario di Ricerca sulla Genomica Funzionale University of Perugia Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9608-4506","authenticated-orcid":false,"given":"Rosario","family":"Donato","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Perugia Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7908-3379","authenticated-orcid":false,"given":"Francesca","family":"Riuzzi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine University of Perugia Perugia Italy"},{"name":"Interuniversity Institute of Myology Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,3,11]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/oncsis.2016.3"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.105"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3829"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12310"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200901052"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0495"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/364501a0"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.09.004"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2002038"},{"key":"e_1_2_8_11_1","first-page":"101","article-title":"RAGE in tissue homeostasis, repair and regeneration","volume":"2013","author":"Sorci G","year":"1833","journal-title":"Biochim Biophys Acta"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-041316-085215"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12350"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.2174\/156652413804486214"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgu176"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2017.07.001"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.092163"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-12880-9"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3388"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy288"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4674"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.11.4880-4894.2004"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/SPC.0000000000000233"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200418704"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.313437"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302895"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds286"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68523"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.09.009"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200420174"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-2364com"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.2000.279.4.R1165"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201607052"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2014.02.002"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1052"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.292"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.136390"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-010-0919-9"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.136259"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.09.001"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2011.286"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/jso.24940"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep29914"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201151"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.3892\/mco.2013.134"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02347-2"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160217"},{"key":"e_1_2_8_48_1","first-page":"5","article-title":"Developmental myosins: expression patterns and functional significance","volume":"15","author":"Schiaffino S","year":"2015","journal-title":"Skelet Muscle"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2010"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12501"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcsm.12561","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12561","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.12561","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12561","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T09:17:25Z","timestamp":1693905445000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.12561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,11]]},"references-count":49,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["10.1002\/jcsm.12561"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.12561","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,11]]},"assertion":[{"value":"2019-05-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}