{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:45:33Z","timestamp":1791989133848,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,9,30]],"date-time":"2018-09-30T00:00:00Z","timestamp":1538265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01 R01AR060209"],"award-info":[{"award-number":["R01 R01AR060209"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01 AR060217"],"award-info":[{"award-number":["R01 AR060217"]}],"id":[{"id":"10.13039\/100000069","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":[[2018,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Cancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour\u2010derived LIF is required for cancer cachexia in mice by knockout of\n                      <jats:italic>Lif<\/jats:italic>\n                      in C26 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A C26\n                      <jats:italic>Lif<\/jats:italic>\n                      null tumour cell line was made using CRISPR\u2010Cas9. Measurements of cachexia were compared in mice inoculated with C26 vs. C26\n                      <jats:sup>\n                        <jats:italic>Lif\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      tumour cells, and atrophy was compared in myotubes treated with medium from C26 vs. C26\n                      <jats:sup>\n                        <jats:italic>Lif\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      tumour cells. Levels of 25 cytokines\/chemokines were compared in serum of mice bearing C26 vs. C26\n                      <jats:sup>\n                        <jats:italic>Lif\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      tumours and in the medium from these tumour cell lines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At study endpoint, C26 mice showed outward signs of sickness while mice with C26\n                      <jats:sup>\n                        <jats:italic>Lif\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      tumours appeared healthy. Mice with C26\n                      <jats:sup>\n                        <jats:italic>Lif\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      tumours showed a 55\u201375% amelioration of body weight loss, muscle loss, fat loss, and splenomegaly compared with mice with C26 tumours (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05). The heart was not affected by LIF levels because the loss of cardiac mass was the same in C26 and C26\n                      <jats:sup>\n                        <jats:italic>Lif\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      tumour\u2010bearing mice. LIF levels in mouse serum was entirely dependent on secretion from the tumour cells. Serum levels of interleukin\u20106 and G\u2010CSF were increased by 79\u2010fold and 68\u2010fold, respectively, in C26 mice but only by five\u2010fold and two\u2010fold, respectively, in C26\n                      <jats:sup>\n                        <jats:italic>Lif\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice, suggesting that interleukin\u20106 and G\u2010CSF increases are dependent on tumour\u2010derived LIF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study shows the first use of CRISPR\u2010Cas9 knockout of a candidate cachexia factor in tumour cells. The results provide direct evidence for LIF as a major cachexia initiating factor for the C26 tumour\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Tumour\u2010derived LIF was also a regulator of multiple cytokines in C26 tumour cells and in C26 tumour\u2010bearing mice. The identification of tumour\u2010derived factors such as LIF that initiate the cachectic process is immediately applicable to the development of therapeutics to treat cachexia. This is a proof of principle for studies that when carried out in human cells, will make possible an understanding of the factors causing cachexia in a patient\u2010specific manner.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.12346","type":"journal-article","created":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:05:16Z","timestamp":1538352316000},"page":"1109-1120","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["Tumour\u2010derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour\u2010bearing mice"],"prefix":"10.1002","volume":"9","author":[{"given":"Susan C.","family":"Kandarian","sequence":"first","affiliation":[{"name":"Department of Health Sciences Boston University  Boston MA 02215 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel 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