Advertisement

Metabolomics

, Volume 9, Issue 3, pp 730–739 | Cite as

Cancer cachexia’s metabolic signature in a murine model confirms a distinct entity

  • Hirak Der-Torossian
  • Scott A. Asher
  • Jason H. Winnike
  • Ashley Wysong
  • Xiaoying Yin
  • Monte S. Willis
  • Thomas M.  O’Connell
  • Marion E. CouchEmail author
Original Article

Abstract

Despite recent consensus definitions, lack of specific biomarkers remains a hurdle towards a more accurate and efficient diagnosis of cancer cachexia, distinguishing cachexia as a separate entity from other wasting syndromes. In a previous pilot study, we have shown that cancer-cachectic mice have a unique metabolic fingerprint with distinct glucose and lipid alterations compared to healthy controls. Further metabolomics studies were carried out to investigate differences in metabolic profiles of cancer-cachectic mice to tumor-bearing non-cachectic mice, calorie-restricted mice, and surgically treated cancer-cachectic mice. CD2F1 mice were divided into: (1) Cachexia Group received cachexia-inducing C26 undifferentiated colon carcinoma cells; (2) Tumor-Burden Group received, non-cachectic, P388 lymphoma cells; (3) Caloric-Restriction Group, remaining cancer-free, but subjected to caloric-restriction; (4) Surgery Group, similar to Cachexia Group, but tumors resected mid-experiment; and (5) Control Group aged intact. Baseline, mid-experiment and final serum samples were collected for 1H NMR spectroscopic analysis. After data reduction, unsupervised principal component analysis and orthogonal projections to latent structures analyses demonstrate that the unique metabolic fingerprint is independent of tumor-burden and distinct from profiles of caloric-restriction and aging. Hyperlipidemia, hyperglycemia, and reduced branched-chain amino acids distinguish cachexia from other groups. Furthermore, the profile of surgically treated mice differs from that of cachectic mice, reverting to a profile more congruent with healthy controls indicating cachexia is amenable to correction where surgical cure is possible. That metabolomic analysis of murine serum is able to differentiate cachexia from tumor-burden and caloric-restriction warrants similar translational investigations in patients to explore cancer cachexia’s unique biomarkers.

Keywords

Metabolomics Cancer Cachexia NMR spectroscopy Caloric-restriction Branched-chain amino acids 

Notes

Acknowledgments

J. Walter Juckett postdoctoral fellowship (H.D.); National Institutes of Health T32 training grant (S.A.); University of North Carolina Program in Translational Science grant (M.C.); General Clinical Research Center grant #RR000046 (T.O.); and National Institute of Environmental Health Sciences grant P30ES10126 (T.O.).

References

  1. Anthony, J. C., Yoshizawa, F., Anthony, T. G., Vary, T. C., Jefferson, L. S., & Kimball, S. R. (2000). Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. Journal of Nutrition, 130, 2413–2419.PubMedGoogle Scholar
  2. Beck, S. A., & Tisdale, M. J. (1989). Nitrogen excretion in cancer cachexia and its modification by a high fat diet in mice. Cancer Research, 49, 3800–3804.PubMedGoogle Scholar
  3. Bennani-Baiti, N., & Walsh, D. (2009). What is cancer anorexia-cachexia syndrome? A historical perspective. Journal of the Royal College of Physicians of Edinburgh, 39, 257–262.PubMedGoogle Scholar
  4. Busquets, S., Alvarez, B., Lopez-Soriano, F. J., & Argiles, J. M. (2002). Branched-chain amino acids: A role in skeletal muscle proteolysis in catabolic states? Journal of Cellular Physiology, 191, 283–289.PubMedCrossRefGoogle Scholar
  5. Busquets, S., Carbo, N., Almendro, V., Figueras, M., Lopez-Soriano, F. J., & Argiles, J. M. (2001). Hyperlipemia: A role in regulating UCP3 gene expression in skeletal muscle during cancer cachexia? FEBS Letters, 505, 255–258.PubMedCrossRefGoogle Scholar
  6. Conti, F., Manganaro, M., & Miccheli, A. (2006). Metabolomics and medical practice. Clinica Terapeutica, 157, 549–552.PubMedGoogle Scholar
  7. Darlington, G. J., Wilson, D. R., & Lachman, L. B. (1986). Monocyte-conditioned medium, interleukin-1, and tumor necrosis factor stimulate the acute phase response in human hepatoma cells in vitro. Journal of Cell Biology, 103, 787–793.PubMedCrossRefGoogle Scholar
  8. Delano, M. J., & Moldawer, L. L. (2006). The origins of cachexia in acute and chronic inflammatory diseases. Nutrition in Clinical Practice: Official Publication of the American Society for Parenteral and Enteral Nutrition, 21, 68–81.CrossRefGoogle Scholar
  9. Eley, H. L., Russell, S. T., & Tisdale, M. J. (2007). Effect of branched-chain amino acids on muscle atrophy in cancer cachexia. Biochemical Journal, 407, 113–120.PubMedCrossRefGoogle Scholar
  10. Evans, W. J., et al. (2008). Cachexia: A new definition. Clinical Nutrition, 27, 793–799.PubMedCrossRefGoogle Scholar
  11. Fearon, K. C., Glass, D. J., & Guttridge, D. C. (2012). Cancer cachexia: Mediators, signaling, and metabolic pathways. Cell Metabolism, 16, 153–166.PubMedCrossRefGoogle Scholar
  12. Fearon, K. C., & Moses, A. G. (2002). Cancer cachexia. International Journal of Cardiology, 85, 73–81.PubMedCrossRefGoogle Scholar
  13. Fearon, K., et al. (2011). Definition and classification of cancer cachexia: An international consensus. Lancet Oncology, 12, 489–495.PubMedCrossRefGoogle Scholar
  14. Feingold, K. R., Soued, M., Serio, M. K., Moser, A. H., Dinarello, C. A., & Grunfeld, C. (1989). Multiple cytokines stimulate hepatic lipid synthesis in vivo. Endocrinology, 125, 267–274.PubMedCrossRefGoogle Scholar
  15. Grunfeld, C., et al. (1989). Persistence of the hypertriglyceridemic effect of tumor necrosis factor despite development of tachyphylaxis to its anorectic/cachectic effects in rats. Cancer Research, 49, 2554–2560.PubMedGoogle Scholar
  16. Holecek, M. (2011). Branched-chain amino acid oxidation in skeletal muscle—physiological and clinical importance of its modulation by reactant availability. Current Nutrition & Food Science, 7, 50–56.CrossRefGoogle Scholar
  17. Holm, E., et al. (1995). Substrate balances across colonic carcinomas in humans. Cancer Research, 55, 1373–1378.PubMedGoogle Scholar
  18. Kotler, D. P. (2000). Cachexia. Annals of Internal Medicine, 133, 622–634.PubMedCrossRefGoogle Scholar
  19. Lawton, K. A., et al. (2008). Analysis of the adult human plasma metabolome. Pharmacogenomics, 9, 383–397.PubMedCrossRefGoogle Scholar
  20. Lecker, S. H., et al. (2004). Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB Journal, 18, 39–51.PubMedCrossRefGoogle Scholar
  21. Lee, S. W., Dai, G., Hu, Z., Wang, X., Du, J., & Mitch, W. E. (2004). Regulation of muscle protein degradation: Coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase. Journal of the American Society of Nephrology, 15, 1537–1545.PubMedCrossRefGoogle Scholar
  22. Lowenstein, J. M., & Goodman, M. N. (1978). The purine nucleotide cycle in skeletal muscle. Federation Proceedings, 37, 2308–2312.PubMedGoogle Scholar
  23. Mahmoud, F. A., & Rivera, N. I. (2002). The role of C-reactive protein as a prognostic indicator in advanced cancer. Current Oncology Reports, 4, 250–255.PubMedCrossRefGoogle Scholar
  24. Mantovani, G., et al. (2010). Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia. Journal of Molecular Medicine, 88, 85–92.PubMedCrossRefGoogle Scholar
  25. Martinez-Outschoorn, U. E., et al. (2011). Energy transfer in “parasitic” cancer metabolism: Mitochondria are the powerhouse and Achilles’ heel of tumor cells. Cell Cycle, 10, 4208–4216.PubMedCrossRefGoogle Scholar
  26. Nelson, K. A., Walsh, D., & Sheehan, F. A. (1994). The cancer anorexia-cachexia syndrome. Journal of Clinical Oncology, 12, 213–225.PubMedGoogle Scholar
  27. Norton, J. A., Gorschboth, C. M., Wesley, R. A., Burt, M. E., & Brennan, M. F. (1985). Fasting plasma amino acid levels in cancer patients. Cancer, 56, 1181–1186.PubMedCrossRefGoogle Scholar
  28. O’Connell, T., et al. (2008). Metabolomic analysis of cancer cachexia reveals distinct lipid and glucose alterations. Metabolomics, 4, 216–225.CrossRefGoogle Scholar
  29. Perlmutter, D. H., Dinarello, C. A., Punsal, P. I., & Colten, H. R. (1986). Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. Journal of Clinical Investigation, 78, 1349–1354.PubMedCrossRefGoogle Scholar
  30. Pickering, W. P., Price, S. R., Bircher, G., Marinovic, A. C., Mitch, W. E., & Walls, J. (2002). Nutrition in CAPD: Serum bicarbonate and the ubiquitin-proteasome system in muscle. Kidney International, 61, 1286–1292.PubMedCrossRefGoogle Scholar
  31. Rieu, I., et al. (2006). Leucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemia. Journal of Physiology, 575, 305–315.PubMedCrossRefGoogle Scholar
  32. Rofe, A. M., Bourgeois, C. S., Coyle, P., Taylor, A., & Abdi, E. A. (1994). Altered insulin response to glucose in weight-losing cancer patients. Anticancer Research, 14, 647–650.PubMedGoogle Scholar
  33. Shaw, J. H., & Wolfe, R. R. (1987). Glucose and urea kinetics in patients with early and advanced gastrointestinal cancer: The response to glucose infusion, parenteral feeding, and surgical resection. Surgery, 101, 181–191.PubMedGoogle Scholar
  34. Strasser, F. (2008). Diagnostic criteria of cachexia and their assessment: Decreased muscle strength and fatigue. Current Opinion in Clinical Nutrition and Metabolic Care, 11, 417–421.PubMedCrossRefGoogle Scholar
  35. Tan, B. H., & Fearon, K. C. (2008). Cachexia: Prevalence and impact in medicine. Current Opinion in Clinical Nutrition and Metabolic Care, 11, 400–407.PubMedCrossRefGoogle Scholar
  36. Tisdale, M. J. (1997). Cancer cachexia: Metabolic alterations and clinical manifestations. Nutrition, 13, 1–7.PubMedCrossRefGoogle Scholar
  37. Tisdale, M. J. (2002). Cachexia in cancer patients. Nature Reviews Cancer, 2, 862–871.PubMedCrossRefGoogle Scholar
  38. van Ravenzwaay, B., et al. (2007). The use of metabolomics for the discovery of new biomarkers of effect. Toxicology Letters, 172, 21–28.PubMedCrossRefGoogle Scholar
  39. Wiklund, S., et al. (2008). Visualization of GC/TOF-MS-based metabolomics data for identification of biochemically interesting compounds using OPLS class models. Analytical Chemistry, 80, 115–122.PubMedCrossRefGoogle Scholar
  40. Yoshizawa, F. (2004). Regulation of protein synthesis by branched-chain amino acids in vivo. Biochemical and Biophysical Research Communications, 313, 417–422.PubMedCrossRefGoogle Scholar
  41. Zhou, Q., Du, J., Hu, Z., Walsh, K., & Wang, X. H. (2007). Evidence for adipose-muscle cross talk: Opposing regulation of muscle proteolysis by adiponectin and fatty acids. Endocrinology, 148, 5696–5705.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Hirak Der-Torossian
    • 1
    • 2
  • Scott A. Asher
    • 3
  • Jason H. Winnike
    • 4
  • Ashley Wysong
    • 5
  • Xiaoying Yin
    • 6
  • Monte S. Willis
    • 7
  • Thomas M.  O’Connell
    • 8
  • Marion E. Couch
    • 1
    • 2
    Email author
  1. 1.Division of Otolaryngology-Head and Neck Surgery, Department of SurgeryUniversity of VermontBurlingtonUSA
  2. 2.Vermont Cancer Center, University of VermontBurlingtonUSA
  3. 3.Division of Otolaryngology-Head and Neck Surgery, Department of SurgeryUniversity of AlabamaBirminghamUSA
  4. 4.David H. Murdock Research InstituteKannapolisUSA
  5. 5.Department of DermatologyStanford UniversityStanfordUSA
  6. 6.Lineberger Comprehensive Cancer Center, University of North CarolinaChapel HillUSA
  7. 7.Department of Pathology and Laboratory MedicineUniversity of North CarolinaChapel HillUSA
  8. 8.LipoScience Inc.RaleighUSA

Personalised recommendations