Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma
Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130F/F knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis. Specifically, exacerbated weight loss, early mortality and reduced muscle and adipose tissue mass were features of the gp130F/F:KrasG12D model, but not parental KrasG12D mice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130F/F:KrasG12D mice revealed the upregulation of IL-6 and STAT3-target genes compared with KrasG12D muscle tissue. These cachectic features of gp130F/F:KrasG12D mice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130F/F:KrasG12D:Stat3-/+ or gp130F/F:KrasG12D:Il6-/- mice, respectively. Furthermore, protein levels of the soluble IL-6 receptor (sIL-6R), which is the central facilitator of IL-6 trans-signalling, were elevated in cachectic muscle from gp130F/F:KrasG12D mice, and the specific blockade of IL-6 trans-signalling, but not classical signalling, with an anti-IL-6R antibody ameliorated cachexia-related characteristics in gp130F/F:KrasG12D mice. Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.Oncogene advance online publication, 28 November 2016; doi:10.1038/onc.2016.437.
|ISBN||1476-5594 (Electronic) 0950-9232 (Linking)|
|Authors||Miller, A.; McLeod, L.; Alhayyani, S.; Szczepny, A.; Watkins, D. N.; Chen, W.; Enriori, P.; Ferlin, W.; Ruwanpura, S.; Jenkins, B. J.|
|Responsible Garvan Author|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/27893707|