Metabolomic analysis of cancer cachexia reveals distinct lipid and glucose alterations
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Cancer cachexia remains a challenging clinical problem with complex pathophysiology and unreliable diagnostic tools. A blood test to detect this metabolic derangement would aid in early treatment of these patients. A 1H NMR-based metabolomics approach was used to determine the unique metabolic fingerprint of cachexia and to search for biomarkers in serum samples taken from an established murine model of cancer cachexia. Male CD2F1 mice received a subcutaneous flank injection of C26 adenocarcinoma cells to induce experimental cancer-related cachexia. Two molecular markers of muscle atrophy, upregulation of the E3 ubiquitin ligase Muscle Ring Finger 1 (MuRF1) and aberrant glycosylation of β-dystroglycan (β-DG), were used to confirm muscle wasting in the tumor-bearing mice. Serum samples were collected for metabolomic analysis during the development of the cachexia: at baseline, when the tumor was palpable, and when the mice demonstrated cachexia. The unsupervised statistical analysis demonstrated a distinct metabolic profile with the onset of cachexia. The critical metabolic changes associated with cachexia included increased levels of very low density lipoprotein (VLDL) and low density lipoprotein (LDL), with decreased serum glucose levels. Regression analysis demonstrated a very high correlation of the presence of aberrant glycosylation of β-DG with the unique metabolic profile of cachexia. This study demonstrates for the first time that metabolomics has potential as a diagnostic tool in cancer cachexia, and in further elucidating simultaneous metabolic pathway alterations due to this syndrome. In addition, variations in VLDL and LDL deserve more investigation as surrogate serum biomarkers for cancer cachexia.
KeywordsMetabolomics Cancer Cachexia NMR spectroscopy Murine model Metabonomics
Grant Support: UNC Translational Science Award; General Clinical Research Center grant #RR000046, and National Institutes of Health T32 training grant, National Institute of Environmental Health Sciences grant P30ES10126.
- Acharyya, S., Butchbach, M. E., Sahenk, Z., Wang, H., Saji, M., Carathers, M., Ringel, M. D., Skipworth, R. J., Fearon, K. C., Hollingsworth, M. A., Muscarella, P., Burghes, A. H., Rafael-Fortney, J. A., & Guttridge, D. C. (2005). Dystrophin glycoprotein complex dysfunction: A regulatory link between muscular dystrophy and cancer cachexia. Cancer Cell, 8, 421–432. doi: 10.1016/j.ccr.2005.10.004.PubMedCrossRefGoogle Scholar
- Birjmohun, R. S., Dallinga-Thie, G. M., Kuivenhoven, J. A., Stroes, E. S., Otvos, J. D., Wareham, N. J., Luben, R., Kastelein, J. J., Khaw, K. T., & Boekholdt, S. M. (2007). Apolipoprotein A-II is inversely associated with risk of future coronary artery disease. Circulation, 116, 2029–2035. doi: 10.1161/CIRCULATIONAHA.107.704031.PubMedCrossRefGoogle Scholar
- Bodine, S. C., Latres, E., Baumhueter, S., Lai, V. K., Nunez, L., Clarke, B. A., Poueymirou, W. T., Panaro, F. J., Na, E., Dharmarajan, K., Pan, Z. Q., Valenzuela, D. M., Dechiara, T. M., Stitt, T. N., Yancopoulos, G. D., & Glass, D. J. (2001). Identification of ubiquitin ligases required for skeletal muscle atrophy. Science, 294, 1704–1708. doi: 10.1126/science.1065874.PubMedCrossRefGoogle Scholar
- Cali, A. M., Zern, T. L., Taksali, S. E., De Oliveira, A. M., Dufour, S., Otvos, J. D., & Caprio, S. (2007). Intrahepatic fat accumulation and alterations in lipoprotein composition in obese adolescents: A perfect proatherogenic state. Diabetes Care, 30, 3093–3098. doi: 10.2337/dc07-1088.PubMedCrossRefGoogle Scholar
- Couch, M., Lai, V., Cannon, T., Guttridge, D., Zanation, A., George, J., Hayes, D. N., Zeisel, S., & Shores, C. (2007). Cancer cachexia syndrome in head and neck cancer patients: Part I. Diagnosis, impact on quality of life and survival, and treatment. Head & Neck, 29, 401–411. doi: 10.1002/hed.20447.CrossRefGoogle Scholar
- Dewys, W. D., Begg, C., Lavin, P. T., Band, P. R., Bennett, J. M., Bertino, J. R., Cohen, M. H., Douglass, H. O., Jr., Engstrom, P. F., Ezdinli, E. Z., Horton, J., Johnson, G. J., Moertel, C. G., Oken, M. M., Perlia, C., Rosenbaum, C., Silverstein, M. N., Skeel, R. T., Sponzo, R. W., & Tormey, D. C. (1980). Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern cooperative oncology group. The American Journal of Medicine, 69, 491–497. doi: 10.1016/S0149-2918(05)80001-3.PubMedCrossRefGoogle Scholar
- Guttridge, D. C., Albanese, C., Reuther, J. Y., Pestell, R. G., & Baldwin, A. S., Jr. (1999). NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Molecular Cell Biology, 19, 5785–5799.Google Scholar
- Strassmann, G., Masui, Y., Chizzonite, R., & Fong, M. (1993). Mechanisms of experimental cancer cachexia. Local involvement of IL-1 in colon-26 tumor. Journal of Immunology, 150, 2341–2345.Google Scholar