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.
Highlights
Cachexia is the widespread loss of muscle and fat that causes death in many cancers
Despite several transcription factors being implicated in different types of cancer cachexia in the literature, including AP-1 [2], C/EBP [22], FOXO [10, 13], NF-B [10, 23], SMAD 2/3 [10], and STAT3 [8, 12], our survey of reporters showed that only the STAT reporter was activated by C26 conditioned medium (CM) (Fig. 1C)
From our survey of transcription factor reporters, including NF-B, C/EBP, FOXO, SMAD, AP-1, and STAT, we found that C26 CM activates only the STAT reporter
Summary
Cachexia is the widespread loss of muscle and fat that causes death in many cancers. Results: Secretion of leukemia inhibitory factor (LIF) by C26 cancer cells activates differential gene expression that results in muscle cell atrophy. Overexpression of a dominant negative Stat3C-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. A C26 conditioned medium (CM) model was used to identify the cytokines secreted and the signaling and transcription factors activated by C26 tumor cells that produce myotube atrophy. We show that leukemia inhibitory factor (LIF) is the cytokine inducing both JAK2/STAT3 and ERK signaling as well as atrophy in myotubes treated with medium from C26 cancer cells. This is the first direct evidence that LIF is an essential regulator of cachexia from C26 tumors
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