Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism

• Published in: Journal of cachexia, sarcopenia and muscle Vol. 10; no. 1; pp. 140 - 154
• Main Authors: Pin, Fabrizio, Barreto, Rafael, Couch, Marion E., Bonetto, Andrea, O'Connell, Thomas M.
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.02.2019; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Anorexia; Antineoplastic Agents - adverse effects; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Cachexia; Cachexia - chemically induced; Cachexia - metabolism; Cachexia - pathology; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Cancer; Cancer therapies; Cell Line, Tumor; Chemotherapy; Dehydrogenases; Energy Metabolism; Fluorouracil - adverse effects; Glucose - metabolism; Laboratory animals; Leucovorin - adverse effects; Lipids; Liver; Liver - drug effects; Liver - metabolism; Male; Metabolism; Metabolites; Metabolomics; Mice; Muscle Strength; Muscle wasting; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Musculoskeletal system; Neoplasms - chemically induced; Neoplasms - metabolism; Neoplasms - pathology; Nitrogen; NMR; Nuclear magnetic resonance; Original; Oxidative stress; Reactive Oxygen Species - metabolism; Receptors, LDL - metabolism; Studies; United States > US; Metabolomics; Chemotherapy; Cachexia; Metabolism; Muscle wasting; Cancer
• ISSN: 2190-5991; 2190-6009
• DOI: 10.1002/jcsm.12360

Background Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer‐induced and chemotherapy‐induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments. Methods The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer‐induced cachexia. In vivo administration of Folfiri (5‐fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy‐induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance‐based and mass spectrometry‐based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling. Results The study involved four groups of CD2F1 male mice (n = 4–5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (−3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (−38% vs. V; P < 0.001). All experimental groups were characterized by an increased systemic glucose demand as evidenced by decreased levels of circulating glucose (−47% in CC vs. V; P < 0.001) and depletion of liver glucose (−51% in CC vs. V; P < 0.001) and glycogen (−74% in CC vs. V; P < 0.001). The cancer‐induced and chemotherapy‐induced cachexia models displayed unique alterations in flux through the tricarboxylic acid cycle and β‐oxidation pathways. Cancer‐induced cachexia was uniquely characterized by a dramatic elevation in low‐density lipoprotein particles (+6.9‐fold vs. V; P < 0.001) and a significant increase in the inflammatory marker, GlycA (+33% vs. V; P < 0.001). Conclusions The results of this study demonstrated for the first time that cancer‐induced and chemotherapy‐induced cachexia is characterized by a number of distinct metabolic derangements. Effective therapeutic interventions for cancer‐induced and chemotherapy‐induced cachexia must take into account the specific metabolic defects imposed by the pathological or pharmacological drivers of cachexia.