D3 | Abstract 11

Annual NUTRIM Symposium 18 November 2020


Characterization of a novel, mouse orthotopic lung cancer model to study lung cancer cachexia.

Wouter R. P. H. van de Worp1, Jan Theys2, Alba Sanz González1, Brent van der Heyden3, Frank Verhaegen3, Annemie M. W. J. Schols1, Ardy van Helvoort1,4 and Ramon C. J. Langen1.

1 Department of Respiratory Medicine, NUTRIM –School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands.
2 Department of Precision Medicine, GROW –School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands.
3 Department of Radiation Oncology (MAASTRO), GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.
4 Danone Nutricia Research, Utrecht, the Netherlands.
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.

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-rasG12D; p53R172HΔG) 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.

NUTRIM | School of Nutrition and Translational Research in Metabolism
NUTRIM aims to contribute to health maintenance and personalised medicine by unraveling lifestyle and disease-induced derangements in metabolism and by developing targeted nutritional, exercise and drug interventions. This is facilitated by a state of the art research infrastructure and close interaction between scientists, clinicians, master and PhD students.