Activation of the SDF1/CXCR4 pathway retards muscle atrophy during cancer cachexia

Cancer cachexia is a life-threatening syndrome that affects most patients with advanced cancers and causes severe body weight loss, with rapid depletion of skeletal muscle. No treatment is available. We analyzed microarray data sets to identify a subset of genes whose expression is specifically alte...

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Bibliographic Details
Published in:	Oncogene Vol. 35; no. 48; pp. 6212 - 6222
Main Authors:	Martinelli, G B, Olivari, D, Re Cecconi, A D, Talamini, L, Ottoboni, L, Lecker, S H, Stretch, C, Baracos, V E, Bathe, O F, Resovi, A, Giavazzi, R, Cervo, L, Piccirillo, R
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-12-2016 Nature Publishing Group
Subjects:	13/105 13/106 13/95 14/35 14/63 38/61 42/109 631/67/2327 64/60 96/1 Adenocarcinoma Adenylate cyclase Animals Apoptosis Atrophy Biomarkers Body weight Body weight loss Cachexia Cachexia - etiology Cachexia - pathology Cancer Cell Biology Cellular signal transduction Chemokine CXCL12 - metabolism Chemokine receptors Complications and side effects CXCR4 protein Cytokines Cytokines - metabolism Development and progression Diabetes mellitus Disease Models, Animal Female Gene Expression Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Genetic aspects GTP-binding protein Health aspects Hepatoma Heterocyclic Compounds - pharmacology Homeostasis Human Genetics Humans Indoles - pharmacology Internal Medicine Isoforms Kidney cancer Male Medicine Medicine & Public Health Mice Muscle fatigue Muscle Fibers, Skeletal - metabolism Muscle Fibers, Skeletal - pathology Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Muscular Atrophy Myotubes Neoplasms - complications Neoplasms - genetics Neoplasms - metabolism Oncology original-article Patients Properties Proteins Pyrroles - pharmacology Rats Receptors, CXCR4 - metabolism SDF-1 protein Signal Transduction - drug effects Skeletal muscle Skeletal system Sunitinib Tibialis anterior muscle Ubiquitin Uremia
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Summary:	Cancer cachexia is a life-threatening syndrome that affects most patients with advanced cancers and causes severe body weight loss, with rapid depletion of skeletal muscle. No treatment is available. We analyzed microarray data sets to identify a subset of genes whose expression is specifically altered in cachectic muscles of Yoshida hepatoma-bearing rodents but not in those with diabetes, disuse, uremia or fasting. Ingenuity Pathways Analysis indicated that three genes belonging to the C-X-C motif chemokine receptor 4 (CXCR4) pathway were downregulated only in muscles atrophying because of cancer: stromal cell-derived factor 1 ( SDF1 ), adenylate cyclase 7 ( ADCY7 ), and p21 protein-activated kinase 1 ( PAK1 ). Notably, we found that, in the Rectus Abdominis muscle of cancer patients, the expression of SDF1 and CXCR4 was inversely correlated with that of two ubiquitin ligases induced in muscle wasting, atrogin-1 and MuRF1 , suggesting a possible clinical relevance of this pathway. The expression of all main SDF1 isoforms ( α , β , γ ) also declined in Tibialis Anterior muscle from cachectic mice bearing murine colon adenocarcinoma or human renal cancer and drugs with anticachexia properties restored their expression. Overexpressing genes of this pathway (that is, SDF1 or CXCR4 ) in cachectic muscles increased the fiber area by 20%, protecting them from wasting. Similarly, atrophying myotubes treated with either SDF1α or SDF1β had greater total protein content, resulting from reduced degradation of overall long-lived proteins. However, inhibiting CXCR4 signaling with the antagonist AMD3100 did not affect protein homeostasis in atrophying myotubes, whereas normal myotubes treated with AMD3100 showed time- and dose-dependent reductions in diameter, until a plateau, and lower total protein content. This further confirms the involvement of a saturable pathway (that is, CXCR4). Overall, these findings support the idea that activating the CXCR4 pathway in muscle suppresses the deleterious wasting associated with cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2016.153