Physiological characterization of a mouse model of cachexia in colorectal liver metastases

Abstract

(cachexia) is severe in patients with colorectal liver metastases because of the large increase in resting energy expenditure but remains understudied because of a lack of suitable preclinical models. Our aim was to characterize a novel preclinical model of cachexia in colorectal liver metastases. We tested the hypothesis that mice with colorectal liver metastases would exhibit cachexia, as evidenced by a reduction in liver-free body mass, muscle mass, and physiological impairment. Twelve-week-old male CBA mice received an intrasplenic injection of Ringer solution (sham) or murine colorectal cancer cells (MoCR) to induce colorectal liver metastases. At end-point (20 -29 days), the livers of MoCR mice were infiltrated completely with metastases, and MoCR mice had reduced liver-free body mass, muscle mass, and epididymal fat mass compared with sham controls (P Ͻ 0.03). MoCR mice exhibited impaired rotarod performance and grip strength (P Ͻ 0.03). Histochemical analyses of tibialis anterior muscles from MoCR mice revealed muscle fiber atrophy and reduced oxidative enzyme activity (P Ͻ 0.001). Adipose tissue remodeling was evident in MoCR mice, with reduced adipocyte diameter and greater infiltration of nonadipocyte tissue (P Ͻ 0.05). These findings reveal the MoCR mouse model exhibits significant cachexia and is a suitable preclinical model of cachexia in colorectal liver metastases. This model should be used for identifying effective treatments for cachexia to improve quality of life and reduce mortality in patients with colorectal liver metastases. muscle wasting; cancer cachexia; muscle weakness; colorectal liver metastases CANCER CACHEXIA IS DEFINED as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support, leading to progressive functional impairment (8). Cachexia occurs in up to 80% of patients with advanced cancers of the gastrointestinal tract, colon, lung, breast, sarcoma, and prostate (33). It is also present early in the progression of gastrointestinal, pancreatic, and lung cancers (33). Cachexia reduces mobility and functional independence and causes severe fatigue, which together reduce overall quality of life (26). Cachexia can also increase the risk of postoperative complications, impair the response to antineoplastic treatments, and result in the eventual failure of respiratory and cardiac muscle function that causes 20 -30% of all cancer-related deaths (33). Unfortunately, there is no Food and Drug Administration-approved treatment for cancer cachexia, and this is due, at least in part, to a lack of suitable preclinical models that closely mimic the human condition for maximizing translational outcomes (24).Colorectal cancer is the third most common cancer worldwide and is the fourth-most common cause of cancer-related death (9). The most frequent complication of colorectal cancer is the development of liver metastases, which occurs in 70% of cases and is the main cause ...

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

“…Many of the models also use solid tumors that do not metastasize in the experimental time frame, whereas in humans, metastases are present at diagnosis in ϳ20 -25% of colorectal cancer patients and develops during the disease in an additional ϳ20% of patients (68). Metastatic models exhibiting cachexia and representing the advanced stage of disease, such as our model of colorectal liver metastases (77), have been characterized and should be used more frequently to aid in the translation of preclinical research. The relative age of animals used in cancer cachexia studies also differs from the patient population, with rodent experiments typically being initiated at ϳ4 -12 wk of age, corresponding to adolescence, young adulthood, whereas cancer cachexia is most prevalent in the aged population (91).…”

Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptake in skeletal muscle

“…C57Bl/10 and mdx mice as well as ob /+ and ob / ob littermates were bred in-house (AMREP Animal Services, Melbourne, VIC, Australia). For PBS and C-26 experiments, 21 wk old CD2F1 mice were used as previously described [21]. nnos +/+ and nnos +/− littermate mice were generated by breeding C57Bl/6 nNOS +/− mice originally obtained from Jackson Laboratories (Bar Harbor, ME).…”

PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia

“…For the metastatic (m)C26 model, 8-wk-old CD2F1 male mice were randomized into sham-treated (serving as controls; n = 8) and tumor-bearing animals (mC26) presenting with intrasplenic injection of 5 3 10 5 C26 cells in sterile saline (n = 8) (30). For the pirinixic acid (WY-14643) experiment, CD2F1 male mice (n = 8) were randomized into 2 groups-namely, mice receiving a regular chow diet and mice fed a diet (Research Diets, New Brunswick, NJ, USA) supplemented with 0.1% WY-14643 (Selleck Chemicals, Houston, TX, USA) (31).…”