Although various lung tumor-bearing animal models have been used to explore underlying mechanisms of cancer cachexia, these models do not recapitulate anatomical and immunological features key to lung cancer and associated muscle wasting. As these shortcomings may hamper translating experimental findings into the clinic, we characterized a syngeneic, orthotopic lung cancer mouse model to study the etiology of lung cancer-induced muscle wasting.

Methods:
Immune competent, male 129S2/Sv mice, 11 weeks old, were randomly allocated to either (1) sham control group or (2) tumor-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-ras^G12D; p53^R172HΔG) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumor growth and muscle volume were assessed using micro cone beam CT imaging. At the end of the study, animals were euthanized and skeletal muscles of the lower hind limbs were collected.

Results: Approximately 60% of the tumor-bearing mice developed cachexia. The cachectic mice showed reduced final body weight (13.7 ± 5.7%) and CT-based muscle mass (13.8 ± 8.1%) compared to sham controls and had a median survival time of 33.5 days post-surgery until humane endpoint. In cachectic mice, markers for proteolysis, both ubiquitin proteasome system (Atrogin-1 and MuRF-1) and autophagy-lysosomal pathway (GABARAPL and Bnip3), were significantly upregulated, whereas markers for protein synthesis (e.g. p-4E-BP1) were significantly decreased. Furthermore, cachectic mice showed increased glucocorticoid signaling indicated by increased expression of direct targets of the glucocorticoid receptor (KLF15 and Glul) compared to sham controls.

Conclusion: We developed an orthotopic model of lung cancer cachexia in immune competent mice. This model will contribute to understanding the underlying mechanisms of lung cancer or treatment-induced cachexia, and can be deployed to test the efficacy of intervention strategies.