title: Activation of the SDF1/CXCR4 pathway retards muscle atrophy during cancer cachexia.
abstract: 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.
authors.affiliation: Department of Oncology, IRCCS - Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: G B
authors.initials: GB
authors.lastname: Martinelli
authors.affiliation: Department of Oncology, IRCCS - Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Olivari
authors.affiliation: Department of Oncology, IRCCS - Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: A D
authors.initials: AD
authors.lastname: Re Cecconi
authors.affiliation: Department of Oncology, IRCCS - Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Talamini
authors.affiliation: San Raffaele Scientific Institute, INSpe, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ottoboni
authors.affiliation: Beth Israel Deaconess Center, Boston, MA, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Lecker
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Stretch
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: V E
authors.initials: VE
authors.lastname: Baracos
authors.affiliation: Department of Surgery and Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: O F
authors.initials: OF
authors.lastname: Bathe
authors.affiliation: Department of Oncology, Tumor Angiogenesis Unit, IRCCS - Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Resovi
authors.affiliation: Department of Oncology, IRCCS - Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Giavazzi
authors.affiliation: Department of Neuroscience, IRCCS - Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Cervo
authors.affiliation: Department of Oncology, IRCCS - Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Piccirillo
mesh_terms: D000818:Animals; D001596:Benzylamines; D015415:Biomarkers; D002100:Cachexia / Q000209:etiology* / Q000473:pathology*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy; D009369:Neoplasms / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib
chemical_list: D001596:Benzylamines; D015415:Biomarkers; D054377:Chemokine CXCL12; D000080027:Cyclams; D016207:Cytokines; D006571:Heterocyclic Compounds; D007211:Indoles; D011758:Pyrroles; D019718:Receptors, CXCR4; C088327:plerixafor; D000077210:Sunitinib