A novel transplantable model of lung cancer associated tissue loss and disrupted muscle regeneration

Abstract

Background: Cancer-associated muscle wasting (CAW), a symptom of cancer 2 cachexia, is associated with approximately 20% of lung cancer deaths, and 3 remains poorly characterized on a mechanistic level. Current animal models for 4 lung cancer-associated cachexia are limited in that they: 1) primarily employ flank 5 transplantation methods, 2) have short survival times not reflective of the patient 6 condition, and 3) are typically performed in young mice not representative of 7 mean patient age. This study investigates a new model for lung cancer-8 associated cachexia that can address these issues and also implicates muscle 9 regeneration as a contributor to CAW. 10 Methods:We used tail vein injection as a method to introduce tumor cells that 11 seed primarily in the lungs of mice. Body composition of tumor bearing mice was 12 longitudinally tracked using magnetic resonance imaging (MRI). These data were 13 combined with histological and molecular assessments of skeletal muscle to 14 provide a complete analysis of muscle wasting. 15Results: In this new lung CAW model we observed 1) progressive loss in whole 16 body weight, 2) progressive loss of lean and fat mass, 3) a circulating 17 cytokine/inflammatory profile similar to that seen in other models of CAW, 4) 18 histological changes associated with muscle wasting, and 5) molecular changes 19 in muscle that implicate suppression of muscle repair/regeneration. Finally, we 20show that survival can be extended without lessening CAW by titrating injected 21 cell number. 22Conclusions: Overall, this study describes a new model of CAW that could be 23 useful for further studies of lung cancer-associated wasting and accompanying 24 changes in the regenerative capacity of muscle. Additionally, this model 25 addresses many recent concerns with existing models such as 26 immunocompetence, location of tumor, and survival time. 27