RT Journal Article
SR Electronic
T1 A novel transplantable model of lung cancer associated tissue loss and disrupted muscle regeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 852442
DO 10.1101/852442
A1 Arneson, Paige C
A1 Ducharme, Alexandra M
A1 Doles, Jason D
YR 2020
UL http://biorxiv.org/content/early/2020/02/04/852442.abstract
AB Background Cancer-associated muscle wasting (CAW), a symptom of cancer cachexia, is associated with approximately 20% of lung cancer deaths, and remains poorly characterized on a mechanistic level. Current animal models for lung cancer-associated cachexia are limited in that they: 1) primarily employ flank transplantation methods, 2) have short survival times not reflective of the patient condition, and 3) are typically performed in young mice not representative of mean patient age. This study investigates a new model for lung cancer-associated cachexia that can address these issues and also implicates muscle regeneration as a contributor to CAW.Methods We used tail vein injection as a method to introduce tumor cells that seed primarily in the lungs of mice. Body composition of tumor bearing mice was longitudinally tracked using NMR-based, echo magnetic resonance imaging (echoMRI). These data were combined with histological and molecular assessments of skeletal muscle to provide a complete analysis of muscle wasting.Results In this new lung CAW model we observed 1) progressive loss in whole body weight, 2) progressive loss of lean and fat mass, 3) a circulating cytokine/inflammatory profile similar to that seen in other models of CAW, 4) histological changes associated with muscle wasting, and 5) molecular changes in muscle that implicate suppression of muscle repair/regeneration. Finally, we show that survival can be extended without lessening CAW by titrating injected cell number.Conclusions Overall, this study describes a new model of CAW that could be useful for further studies of lung cancer-associated wasting and accompanying changes in the regenerative capacity of muscle. Additionally, this model addresses many recent concerns with existing models such as immunocompetence, tumor location, and survival time.CAWCancer associated muscle wastingLLCLewis lung carcinomaCLNCentrally-located nucleiTATibialis AnteriorqPCRquantitative polymerase chain reactionechoMRIecho magnetic resonance imagingH&EHematoxylin and EosinDAPI4′,6-diamidino-2-phenylindoleRNAseqRibonucleic acid sequencingPCAPrinciple Component AnalysisGRGastrocnemiusSEMStandard Error of the MeanSDStandard DeviationTNFαTumor Necrosis Factor AlphaIL6Interleukin 6GEMMsGenetically Engineered Mouse ModelsIACUCInstitutional Animal Care and Use CommitteeLIXC-X-C Motif Ligand 5VEGFVascular Endothelial Growth FactorTrim63Muscle RING Finger 1 (MuRF1)Fbxo32F-box Only Protein 32Pax7Paired Box 7MyoD1Myogenic Differentiation 1NIHNational Institutes of HealthNIAMSNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNCINational Cancer InstituteRSTPRegenerative Sciences Training Program