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Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia

BACKGROUND: Eighty per cent of United States advanced cancer patients faces a worsened prognosis due to cancer‐associated cachexia. Inflammation is one driver of muscle atrophy in cachexia, and skeletal muscle‐resident immune cells could be a source of inflammation. This study explores the efficacy...

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Autores principales: Widner, D. Brooke, Liu, Chun, Zhao, Qingxia, Sharp, Sarah, Eber, Matthew R., Park, Sun H., Files, D. Clark, Shiozawa, Yusuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350201/
https://www.ncbi.nlm.nih.gov/pubmed/34008339
http://dx.doi.org/10.1002/jcsm.12714
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author Widner, D. Brooke
Liu, Chun
Zhao, Qingxia
Sharp, Sarah
Eber, Matthew R.
Park, Sun H.
Files, D. Clark
Shiozawa, Yusuke
author_facet Widner, D. Brooke
Liu, Chun
Zhao, Qingxia
Sharp, Sarah
Eber, Matthew R.
Park, Sun H.
Files, D. Clark
Shiozawa, Yusuke
author_sort Widner, D. Brooke
collection PubMed
description BACKGROUND: Eighty per cent of United States advanced cancer patients faces a worsened prognosis due to cancer‐associated cachexia. Inflammation is one driver of muscle atrophy in cachexia, and skeletal muscle‐resident immune cells could be a source of inflammation. This study explores the efficacy of cancer activated skeletal muscle‐resident mast cells as a biomarker and mediator of cachexia. METHODS: Individual gene markers for immune cells were assessed in a publicly available colon carcinoma cohort of normal (n = 3), moderate cachexia (n = 3), and severe cachexia (n = 4) mice. Lewis lung carcinoma (LL/2) cells induced cachexia in C57BL/6 mice, and a combination of toluidine blue staining, immunofluorescence, quantitative polymerase chain reaction, and western blots measured innate immune cell expression in hind limb muscles. In vitro measurements included C2C12 myotube diameter before and after treatment with media from primary murine mast cells activated with LL/2 conditioned media. To assess translational potential in human samples, innate immune cell signatures were assessed for correlation with skeletal muscle atrophy and apoptosis, dietary excess, and cachexia signatures in normal skeletal muscle tissue. Gene set enrichment analysis was performed with innate immune cell signatures in publicly available cohorts for upper gastrointestinal (GI) cancer and pancreatic ductal adenocarcinoma (PDAC) patients (accession: GSE34111 and GSE130563, respectively). RESULTS: Individual innate immunity genes (TPSAB1 and CD68) showed significant increases in severe cachexia (weight loss > 15%) mice in a C26 cohort (GSE24112). Induction of cachexia in C57BL/6 mice with LL/2 subcutaneous injection significantly increased the number of activated skeletal muscle‐resident degranulating mast cells. Murine mast cells activated with LL/2 conditioned media decreased C2C12 myotube diameter (P ≤ 0.05). Normal human skeletal muscle showed significant positive correlations between innate immune cell signatures and muscle apoptosis and atrophy, dietary excess, and cachexia signatures. The mast cell signature was up‐regulated (positive normalized enrichment score and false discovery rate ≤ 0.1) in upper GI cachectic patients (n = 12) compared with control (n = 6), as well as in cachectic PDAC patients (n = 17) compared with control patients (n = 16). CONCLUSIONS: Activated skeletal muscle‐resident mast cells are enriched in cachectic muscles, suggesting skeletal‐muscle resident mast cells may serve as a biomarker and mediator for cachexia development to improve patient diagnosis and prognosis.
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spelling pubmed-83502012021-08-15 Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia Widner, D. Brooke Liu, Chun Zhao, Qingxia Sharp, Sarah Eber, Matthew R. Park, Sun H. Files, D. Clark Shiozawa, Yusuke J Cachexia Sarcopenia Muscle Original Articles BACKGROUND: Eighty per cent of United States advanced cancer patients faces a worsened prognosis due to cancer‐associated cachexia. Inflammation is one driver of muscle atrophy in cachexia, and skeletal muscle‐resident immune cells could be a source of inflammation. This study explores the efficacy of cancer activated skeletal muscle‐resident mast cells as a biomarker and mediator of cachexia. METHODS: Individual gene markers for immune cells were assessed in a publicly available colon carcinoma cohort of normal (n = 3), moderate cachexia (n = 3), and severe cachexia (n = 4) mice. Lewis lung carcinoma (LL/2) cells induced cachexia in C57BL/6 mice, and a combination of toluidine blue staining, immunofluorescence, quantitative polymerase chain reaction, and western blots measured innate immune cell expression in hind limb muscles. In vitro measurements included C2C12 myotube diameter before and after treatment with media from primary murine mast cells activated with LL/2 conditioned media. To assess translational potential in human samples, innate immune cell signatures were assessed for correlation with skeletal muscle atrophy and apoptosis, dietary excess, and cachexia signatures in normal skeletal muscle tissue. Gene set enrichment analysis was performed with innate immune cell signatures in publicly available cohorts for upper gastrointestinal (GI) cancer and pancreatic ductal adenocarcinoma (PDAC) patients (accession: GSE34111 and GSE130563, respectively). RESULTS: Individual innate immunity genes (TPSAB1 and CD68) showed significant increases in severe cachexia (weight loss > 15%) mice in a C26 cohort (GSE24112). Induction of cachexia in C57BL/6 mice with LL/2 subcutaneous injection significantly increased the number of activated skeletal muscle‐resident degranulating mast cells. Murine mast cells activated with LL/2 conditioned media decreased C2C12 myotube diameter (P ≤ 0.05). Normal human skeletal muscle showed significant positive correlations between innate immune cell signatures and muscle apoptosis and atrophy, dietary excess, and cachexia signatures. The mast cell signature was up‐regulated (positive normalized enrichment score and false discovery rate ≤ 0.1) in upper GI cachectic patients (n = 12) compared with control (n = 6), as well as in cachectic PDAC patients (n = 17) compared with control patients (n = 16). CONCLUSIONS: Activated skeletal muscle‐resident mast cells are enriched in cachectic muscles, suggesting skeletal‐muscle resident mast cells may serve as a biomarker and mediator for cachexia development to improve patient diagnosis and prognosis. John Wiley and Sons Inc. 2021-05-18 2021-08 /pmc/articles/PMC8350201/ /pubmed/34008339 http://dx.doi.org/10.1002/jcsm.12714 Text en © 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Widner, D. Brooke
Liu, Chun
Zhao, Qingxia
Sharp, Sarah
Eber, Matthew R.
Park, Sun H.
Files, D. Clark
Shiozawa, Yusuke
Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia
title Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia
title_full Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia
title_fullStr Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia
title_full_unstemmed Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia
title_short Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia
title_sort activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350201/
https://www.ncbi.nlm.nih.gov/pubmed/34008339
http://dx.doi.org/10.1002/jcsm.12714
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