| Autor: |
Miller A; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; General and Respiratory Medicine, Monash Medical Centre, Monash Health, Clayton, Victoria, Australia., McLeod L; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia., Alhayyani S; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.; Department of Biological Sciences, Rabigh College of Science and Art, King Abdulaziz University, Jeddah, Saudi Arabia., Szczepny A; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia., Watkins DN; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Chen W; Department of Physiology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia., Enriori P; Department of Physiology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia., Ferlin W; NovImmune SA, Geneva, Switzerland., Ruwanpura S; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia., Jenkins BJ; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia. |
| Abstrakt: |
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 gp130 F/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 gp130 F/F :Kras G12D model, but not parental Kras G12D mice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130 F/F :Kras G12D mice revealed the upregulation of IL-6 and STAT3-target genes compared with Kras G12D muscle tissue. These cachectic features of gp130 F/F :Kras G12D mice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130 F/F :Kras G12D :Stat3 -/+ or gp130 F/F :Kras G12D :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 gp130 F/F :Kras G12D 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 gp130 F/F :Kras G12D 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. |
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