{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T20:18:42Z","timestamp":1783455522238,"version":"3.55.0"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015766","name":"Danone Nutricia Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015766","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":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour\u2010bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle\u2010specific alterations associated with human lung cancer cachexia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Immune competent, 11\u00a0weeks old male 129S2\/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour\u2010bearing group. Syngeneic lung epithelium\u2010derived adenocarcinoma cells (<jats:italic>K\u2010ras<\/jats:italic><jats:sup><jats:italic>G12D<\/jats:italic><\/jats:sup>; <jats:italic>p53<\/jats:italic><jats:sup><jats:italic>R172H\u0394G<\/jats:italic><\/jats:sup>) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two\u2010third of the tumour\u2010bearing mice developed cachexia based on predefined criteria. Final body weight (\u221213.7\u00a0\u00b1\u00a05.7%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), muscle mass (\u221213.8\u00a0\u00b1\u00a08.1%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and muscle strength (\u221225.5\u00a0\u00b1\u00a010.5%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) were reduced in cachectic mice compared with sham controls and median survival time post\u2010surgery was 33.5\u00a0days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (<jats:italic>Fbxo32<\/jats:italic> and <jats:italic>Trim63<\/jats:italic>) and autophagy\u2010lysosomal pathway (<jats:italic>Gabarapl1<\/jats:italic> and <jats:italic>Bnip3<\/jats:italic>), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E\u2010BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin\u20102 (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and CXCL1\/KC (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) expression levels in blood plasma and increased mRNA expression of I\u03baB\u03b1 (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal muscle strongly mirrored alterations observed in muscle biopsies of patients with lung cancer cachexia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We developed an orthotopic model of lung cancer cachexia in immune competent mice. Because this model simulates key aspects specific to cachexia in lung cancer patients, it is highly suitable to further investigate the underlying mechanisms of lung cancer cachexia and to test the efficacy of novel intervention strategies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13222","type":"journal-article","created":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T05:41:00Z","timestamp":1680846060000},"page":"1410-1423","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A novel orthotopic mouse model replicates human lung cancer cachexia"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8672-3247","authenticated-orcid":false,"given":"Wouter R.P.H.","family":"van de Worp","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine, NUTRIM \u2013 School of Nutrition and Translational Research in Metabolism Maastricht University Medical Center+  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Theys","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, GROW \u2013 School for Oncology and Developmental Biology Maastricht University Medical Center+  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba Sanz","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, NUTRIM \u2013 School of Nutrition and Translational Research in Metabolism Maastricht University Medical Center+  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent","family":"van der Heyden","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology (MAASTRO), GROW \u2013 School for Oncology and Developmental Biology Maastricht University Medical Centre+  Maastricht The 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