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 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 cancerassociated 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.

Mitochondrial Dysfunction in Cancer Cachexia: Impact on Muscle Health and Regeneration

“…In addition to the altered energy metabolism, and likely interconnected with the latter, delayed muscle regeneration has been shown to take place in both tumor-bearing animals and cancer patients [20][21][22][23], with the transcription factor NF-κB [18] and enhanced activation of ERK stress kinase playing a role [17]. Similarly, overexpression in myogenic precursors of Twist1, a transcription factor associated with the malignant progression of several tumors, or of the zinc transporter ZIP14, is associated with impaired differentiation and muscle atrophy in preclinical models of cancer cachexia [24,25].…”

Anticachectic regulator analysis reveals Perp-dependent antitumorigenic properties of 3-methyladenine in pancreatic cancer

“…Cell proliferation and cell death were measured by live cell analysis (Incucyte ZOOM Live-Cell Imaging System, Essen Bioscience) as previously described ( 42 ).…”

“…EchoMRI (magnetic resonance imaging) Body Composition Analyzer (Echo Medical Systems, Houston, USA) was used for longitudinal body composition analyses as previously described (42). Mice were regularly measured for lean mass, fat mass, and body weight.…”

“…RNA extracted from cells and tissues was submitted to the Mayo Clinic Medical Genome Facility where RNA quality was determined using the Fragment Analyzer from AATI. Library preparation, sequencing and analyses were performed as described previously (42). The accession numbers are PRJNA773714, PRJNA773111, PRJNA773410 on NCBI SRA.…”

Nutrition challenges of cancer cachexia

“…In addition to those above, novel models used in pivotal mechanistic studies have included cell implantation of variant isolates of lung adenocarcinoma, 116 renal cell carcinoma, 117 ovarian cancer, 118 and other primary tumors (reviewed in Tomasin et al 119 ), as well as genetic models of lung cancer 120,121 and others, but there exist only a handful of studies for each to date. Given the prevalence of cachexia in patients with metastatic disease, investigators have also sought to model cachexia in mice with induced metastasis.…”