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Exploring the contribution of the liver to cancer cachexia development.
J. Cachexia Sarcopenia Muscle, 1387 (2019)
Traditionally, skeletal muscle and adipose tissue have been the focus of
research on cancer cachexia. Recent studies suggest that cancer
cachexia (CC) is a multi‐organ syndrome which involves not only the
direct effects of tumour‐derived cachexia‐inducing factors on target
organs but also the crosstalk of these dysfunctional organs. Despite its
central role in other metabolic diseases, the liver has received little
attention in the context of CC. However, CC is associated with systemic
inflammation, and the activation of the hepatic acute phase response
(APR) is well‐documented in cachectic patients. Serum amyloid A 1 and 2
(SAA 1/2) are classical APR proteins that are mainly produced by the
liver and strongly induced in response to inflammatory cytokines. To
assess the potential contribution of SAA to tissue wasting in vitro,
we treated 3T3‐L1 adipocytes and C2C12 myotubes with recombinant SAA1.
While lipolysis rates remained unaffected, we found a significant
reduction in myotube diameter in response to SAA1 treatment, indicative
of an atrophic effect. Next, we addressed the contribution of SAA 1/2 to
cachexia development in vivo using a liver‐specific knock‐down
(KD) approach. For this purpose, we injected an AAV‐miRNA targeting
SAA1/2 or an AAV‐control‐miRNA into C26 tumour bearing mice. Despite a
four‐fold reduction in circulating serum levels in the SAA1/2 KD group,
SAA1 was still highly up‐regulated in tumour bearing mice and no
differences were observed in cachexia progression. In order to define
novel liver‐secreted factors that can potentially impact cachexia
development, we integrated hepatocyte specific RNAseq and serum proteome
analyses of C26 cachectic animals and observed a high degree of
overlap. We are currently functionally characterizing a panel of these
hepatocyte‐secreted proteins in order to investigate their potential
adipocyte lipolysis and/or myotube atrophy‐mediating properties. These
studies might contribute to a better understanding of the
pathophysiology of CC and the liver‐specific contribution to its
development.
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Publication type
Article: Journal article
Document type
Meeting abstract
ISSN (print) / ISBN
2190-5991
e-ISSN
2190-6009
Quellenangaben
Pages: 1387
Publisher
Springer
Publishing Place
Heidelberg
Non-patent literature
Publications
Reviewing status
Peer reviewed