期刊
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
卷 12, 期 4, 页码 1079-1097出版社
WILEY
DOI: 10.1002/jcsm.12714
关键词
Cancer‐ associated cachexia; Mast cells; Degranulation; Innate immunity; Skeletal muscle
资金
- National Cancer Institute [R01-CA238888, R44-CA203184]
- Department of Defence [W81XWH-17-1-0541, W81XWH-19-1-0045]
- METAvivor (METAvivor Research Award)
- Wake Forest Baptist Comprehensive Cancer Center Internal Pilot Funding
- National Cancer Institute's Cancer Center Support Grant [P30-CA012197]
- Wake Forest Baptist Comprehensive Cancer Center Cell Engineering Shared Resource and Flow Cytometry Shared Resource - National Cancer Institute's Cancer Center Support Grant [P30-CA012197]
This study found that activated skeletal muscle-resident mast cells are enriched in cachectic muscles, suggesting that skeletal muscle-resident mast cells may serve as a biomarker and mediator for cachexia development to improve patient diagnosis and prognosis.
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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