Abstract
SUMMARYCancer cachexia describes the progressive skeletal muscle wasting and weakness that is associated with many cancers. It impairs quality of life and accounts for >20% of all cancer-related deaths. The main outcome that affects quality of life and mortality is loss of skeletal muscle function and so preclinical models should exhibit similar functional impairments in order to maximize translational outcomes. Mice bearing colon-26 (C-26) tumors are commonly used in cancer cachexia studies but few studies have provided comprehensive assessments of physiological and metabolic impairment, especially those factors that impact quality of life. Our aim was to characterize functional impairments in mildly and severely affected cachectic mice, and determine the suitability of these mice as a preclinical model. Metabolic abnormalities are also evident in cachectic patients and we investigated whether C-26-tumor-bearing mice had similar metabolic aberrations. Twelve-week-old CD2F1 mice received a subcutaneous injection of PBS (control) or C-26 tumor cells. After 18–20 days, assessments were made of grip strength, rotarod performance, locomotor activity, whole body metabolism, and contractile properties of tibialis anterior (TA) muscles (in situ) and diaphragm muscle strips (in vitro). Injection of C-26 cells reduced body and muscle mass, and epididymal fat mass. C-26-tumor-bearing mice exhibited lower grip strength and rotarod performance. Locomotor activity was impaired following C-26 injection, with reductions in movement distance, duration and speed compared with controls. TA muscles from C-26-tumor-bearing mice had lower maximum force (−27%) and were more susceptible to fatigue. Maximum specific (normalized) force of diaphragm muscle strips was reduced (−10%) with C-26 injection, and force during fatiguing stimulation was also lower. C-26-tumor-bearing mice had reduced carbohydrate oxidation and increased fat oxidation compared with controls. The range and consistency of functional and metabolic impairments in C-26-tumor-bearing mice confirm their suitability as a preclinical model for cancer cachexia. We recommend the use of these comprehensive functional assessments to maximize the translation of findings to more accurately identify effective treatments for cancer cachexia.
Highlights
Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass with or without loss of fat mass that leads to progressive functional impairment (Fearon et al, 2011)
Cumulative food intake was significantly lower from day 10 in PF controls compared with PBS mice fed ad libitum, and in severely cachectic C-26-tumor-bearing mice compared with mildly cachectic tumor-bearing mice (Fig. 1D)
The characterization of functional and metabolic impairments in C-26-tumor-bearing mice confirms their suitability as a preclinical model for cancer cachexia
Summary
Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass with or without loss of fat mass that leads to progressive functional impairment (Fearon et al, 2011). Cachexia is present in up to 80% of patients with advanced cancer and in 60-80% of individuals diagnosed with gastrointestinal, pancreatic and lung cancers (Bruera, 1997). It decreases mobility, physical activity and functional independence, leading to an overall reduction in quality of life (Dahele et al, 2007; Fouladiun et al, 2007). Treatments are needed urgently to improve patient quality of life and reduce mortality
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