{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T01:15:59Z","timestamp":1789434959374,"version":"build-2803163510"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T00:00:00Z","timestamp":1695168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006001","name":"Ateneo de Manila University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006001","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":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Causes and mechanisms underlying cancer cachexia are not fully understood, and currently, no therapeutic approaches are available to completely reverse the cachectic phenotype. Interleukin\u20106 (IL\u20106) has been extensively described as a key factor in skeletal muscle physiopathology, exerting opposite roles through different signalling pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed a three\u2010dimensional ex vivo muscle engineered tissue (X\u2010MET) to model cancer\u2010associated cachexia and to study the effectiveness of selective inhibition of IL\u20106 transignalling in counteracting the cachectic phenotype. Conditioned medium (CM) derived from C26 adenocarcinoma cells was used as a source of soluble factors contributing to the establishment of cancer cachexia in the X\u2010MET model. A dose of 1.2\u00a0ng\/mL of glycoprotein\u2010130 fused chimaera (gp130Fc) was added to cachectic culture medium to neutralize IL\u20106 transignalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      C26\u2010conditioned medium induced a cachectic\u2010like phenotype in the X\u2010MET, leading to a decline of muscle mass (\u221260%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001), a reduction in myosin expression (\u221292.4%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.005) and a reduction of the contraction frequency spectrum (\u221294%). C26\u2010conditioned medium contains elevated amounts of IL\u20106 (8.61\u00a0\u00b1\u00a04.09\u00a0pg\/mL) and IL6R (56.85\u00a0\u00b1\u00a010.96\u00a0pg\/mL). These released factors activated the signal transducer and activator of transcription 3 (STAT3) signalling in the C26_CM X\u2010MET system (phosphorylated STAT3\/TOTAL +54.6%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.005), which in turn promote an enhancement of Il\u20106 (+69.2%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) and Il6r (+43%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) gene expression, suggesting the induction of a feed\u2010forward loop. The selective neutralization of IL\u20106 transignalling, by gp130Fc, in C26_CM X\u2010MET prevented the hyperactivation of STAT3 (\u221255.8%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.005), countered the reduction of cross\u2010sectional area (+28.2%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) and reduced the expression of proteolytic factors including muscle ring finger\u20101 (\u221288%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.005) and ATROGIN1 (\u221292%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05), thus preserving the robustness and increasing the contractile force (+20%) of the three\u2010dimensional muscle system. Interestingly, the selective inhibition of IL\u20106 transignalling modulated gene regulatory networks involved in myogenesis and apoptosis, normalizing the expression of pro\u2010apoptotic miRNAs, including miR\u201031 (\u221253.2%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) and miR\u201034c (\u221265%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.005), and resulting in the reduction of apoptotic pathways highlighted by the sensible reduction of cleaved caspase 3 (\u221292.5%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.005) in gp130Fc\u2010treated C26_CM X\u2010MET.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>IL\u20106 transignalling appeared as a promising target to counter cancer cachexia\u2010related alterations. The X\u2010MET model has proven to be a reliable drug\u2010screening tool to identify novel therapeutic approaches and to test them in preclinical studies, significantly reducing the use of animal models.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13329","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T03:08:40Z","timestamp":1695179320000},"page":"2550-2568","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Modelling three\u2010dimensional cancer\u2010associated cachexia and therapy: The molecular basis and therapeutic potential of interleukin\u20106 transignalling blockade"],"prefix":"10.1002","volume":"14","author":[{"given":"Marianna","family":"Cosentino","sequence":"first","affiliation":[{"name":"DAHFMO\u2010Unit of Histology and Medical Embryology Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia \u2013 Fondazione Cenci Bolognetti  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Forcina","sequence":"additional","affiliation":[{"name":"DAHFMO\u2010Unit of Histology and Medical Embryology Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia \u2013 Fondazione Cenci Bolognetti  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Zouhair","sequence":"additional","affiliation":[{"name":"DAHFMO\u2010Unit of Histology and Medical Embryology Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia \u2013 Fondazione Cenci Bolognetti  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovica","family":"Apa","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desir\u00e8e","family":"Genovese","sequence":"additional","affiliation":[{"name":"DAHFMO\u2010Unit of Histology and Medical Embryology Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia \u2013 Fondazione Cenci Bolognetti  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Boccia","sequence":"additional","affiliation":[{"name":"DAHFMO\u2010Unit of Histology and Medical Embryology Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia \u2013 Fondazione Cenci Bolognetti  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Rizzuto","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2944-9739","authenticated-orcid":false,"given":"Antonio","family":"Musar\u00f2","sequence":"additional","affiliation":[{"name":"DAHFMO\u2010Unit of Histology and Medical Embryology Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia \u2013 Fondazione Cenci Bolognetti  Rome Italy"},{"name":"Scuola Superiore di Studi Avanzati Sapienza (SSAS) Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.05.018"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.06.011"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/SPC.0000000000000091"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-016-2285-z"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(85)80097-3"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep01420"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-37553-8"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/s22186878"},{"key":"e_1_2_8_10_1","doi-asserted-by":"crossref","unstructured":"PisuS ApaL CosentinoM Musar\u00f2A RizzutoE Del PreteZ.Measuring the X\u2010MET's maximum power: a preliminary study. 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