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SKELETAL MUSCLE-RESIDENT MAST CELL DEGRANULATION MAY BE A MARKER BUT NOT A THERAPEUTIC TARGET FOR CANCER-ASSOCIATED CACHEXIA

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abstract
BACKGROUND: Cancer-associated cachexia is a widespread issue affecting up to 80% of all advanced cancer patients. Cachectic patients face decreased systemic muscle function and increased morbidity. There are currently no effective standard treatments for cancer-associated cachexia, and early detection of at-risk patients remains a challenge. Inflammation is an established promotor of the characteristic loss of muscle mass and function in cancer-associated cachexia. This study sought to determine if inflammation promoting mast cells within the skeletal muscle may serve as a novel marker of cachexia development and/or a potential therapeutic target for cachexia treatment. RESULTS: Initial assessment of individual immune cell gene expression in a murine cachectic cohort showed enrichment of mast cell tryptase genes in cachectic mice compared to normal controls. In an in vivo model, Lewis Lung Carcinoma (LL/2) cells induced cachexia in C57BL/6 mice, and mast cell degranulation was significantly increased in the skeletal muscles of these mice. LL/2 activated primary murine mast cells in vitro decreased C2C12 murine myotube diameter following 24h treatment. Publicly available patient data showed mast cell activation signatures positively correlated with skeletal muscle apoptosis and atrophy signals in normal skeletal muscle tissue. Moreover, gene set enrichment analysis showed enrichment of the mast cell activation signature in two cachexia patient cohorts for upper gastrointestinal cancer and pancreatic ductal adenocarcinoma. However, daily ketotifen mast cell stabilizer treatment did not prevent cachexia development in LL/2-bearing C57BL/6 mice. Likewise, mast cell deficiency did not prevent loss of body and muscle mass in LL/2-bearing mast cell deficient W-sh mice. Mast cell reconstitution into W-sh mice, also confirmed there was no significant difference in muscle mass respective of mast cell status. CONCLUSION: Skeletal muscle-resident mast cell degranulation is increased in cachectic skeletal muscle. However, mast cells are not the sole driver of cancer-associated cachexia, and targeting mast cells did not prevent cachexia development in the LL/2 model in vivo. Mast cell activation status within the skeletal muscle may serve as a marker of cachexia development. It is likely a combination of treatments, (i.e. targeting multiple immune cells simultaneously), will be needed for effective cachexia treatment.
subject
cancer-associated cachexia
degranulation
innate immunity
Lewis Lung Carcinoma
mast cells
skeletal muscle
contributor
Widner, Danielle Brooke (author)
Shiozawa, Yusuke (committee chair)
Peters, Christopher (committee member)
Criswell, Tracy (committee member)
Kerr, Bethany (committee member)
Watabe, Kounosuke (committee member)
date
2021-01-13T09:35:31Z (accessioned)
2021 (issued)
degree
Cancer Biology (discipline)
2023-01-12 (liftdate)
embargo
2023-01-12 (terms)
identifier
http://hdl.handle.net/10339/97964 (uri)
language
en (iso)
publisher
Wake Forest University
title
SKELETAL MUSCLE-RESIDENT MAST CELL DEGRANULATION MAY BE A MARKER BUT NOT A THERAPEUTIC TARGET FOR CANCER-ASSOCIATED CACHEXIA
type
Dissertation

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