title: A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia.
abstract: Cachexia is an exacerbating event in many types of cancer that is strongly associated with a poor prognosis. We have identified cytokine, signaling, and transcription factors that are required for cachexia in the mouse C26 colon carcinoma model of cancer. C2C12 myotubes treated with conditioned medium from C26 cancer cells induced atrophy and activated a STAT-dependent reporter gene but not reporter genes dependent on SMAD, FOXO, C/EBP, NF-κB, or AP-1. Of the gp130 family members IL-11, IL-6, oncostatin M (OSM), and leukemia inhibitory factor (LIF), only OSM and LIF were sufficient to activate the STAT reporter in myotubes. LIF was elevated in C26 conditioned medium (CM), but IL-6, OSM, TNFα, and myostatin were not. A LIF-blocking antibody abolished C26 CM-induced STAT reporter activation, STAT3 phosphorylation, and myotube atrophy but blocking antibodies to IL-6 or OSM did not. JAK2 inhibitors also blocked C26 CM-induced STAT reporter activation, STAT3 phosphorylation, and atrophy in myotubes. LIF at levels found in the C26 CM was sufficient for STAT reporter activation and atrophy in myotubes. In vivo, an increase in serum LIF preceded the increase in IL-6 in mice with C26 tumors. Overexpression of a dominant negative Stat3Cβ-EGFP gene in myotubes and in mouse muscle blocked the atrophy caused by C26 CM or C26 tumors, respectively. Taken together, these data support an important role of LIF-JAK2-STAT3 in C26 cachexia and point to a therapeutic approach for at least some types of cancer cachexia.
authors.affiliation: From the Department of Health Sciences, Boston University, Boston, Massachusetts 02215.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Seto
authors.affiliation: From the Department of Health Sciences, Boston University, Boston, Massachusetts 02215.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Kandarian
authors.affiliation: From the Department of Health Sciences, Boston University, Boston, Massachusetts 02215 rjackman@bu.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Jackman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002100:Cachexia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D048429:Cell Size; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053683:Oncostatin M / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; C508352:Osm protein, mouse; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D018808:Transcription Factor AP-1; C485184:enhanced green fluorescent protein; D053683:Oncostatin M; D049452:Green Fluorescent Proteins; D008156:Luciferases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2
keywords: C26 colon carcinoma; JAK; STAT3; cancer cachexia; colorectal cancer; leukemia inhibitory factor (LIF); muscle atrophy; skeletal muscle