Metabolomic analysis of cancer cachexia reveals distinct lipid and glucose alterations

Abstract

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 1 H 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 b-dystroglycan (b-DG), were used to confirm muscle wasting in the tumorbearing 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 b-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.

Lung injury-induced skeletal muscle wasting in aged mice is linked to alterations in long chain fatty acid metabolism

“…In healthy mice challenged with cancer (no cachexia/muscle loss), cancer cachexia (early and late time points), calorie restriction-induced muscle loss, and a control group, NMR analysis of serum identified distinct profiles of the cancer cachexia compared to other groups (hyperlipidemia, hyperglycemia, reduced branched-chain amino acids) (Der-Torossian et al 2013). While these findings confirmed previous studies finding increases in cancer-cachexia plasma (O'Connell et al 2008), they offered a proof that cure (by surgical resection) paralleled predictable resolution of these changes (Der-Torossian et al 2013). In another model of cancer cachexia, incubation of human muscle cells with cachectic conditioned media led to upregulation of fatty acid metabolism pathways and in increase in acyl-carnitines.…”

Metabolic Signatures Imaged in Cancer-Induced Cachexia

“…Atrogin-1 and MuRF1 are skeletal muscle specific ubiquitin ligases involved in the ubiquitin proteasome pathway and essential in the development of muscle atrophy (8, 9). Decreased serum triglycerides and increased LDL have also been previously associated with cachexia (11, 12). Collectively these data confirmed the induction of cachexia in MAC16 tumor-bearing mice.…”

“…Atrogin-1 and MuRF1 are two skeletal muscle specific ubiquitin ligases required in protein breakdown (8), and the expression levels of these ligases increases with cachexia, and (5, 8–10). The presence of cachexia was additionally confirmed by the analysis of lipid content in serum from cachectic and non-cachectic tumor bearing mice (11, 12). …”

Understanding cancer-induced cachexia

“…1 H MRS has been applied to identify cachexia biomarkers in the sera of C26 adenocarcinoma-bearing mice [19]. Increased amounts of very-low-density and low-density lipoproteins were detected along with decreased glucose levels [19].…”

“…1 H MRS has been applied to identify cachexia biomarkers in the sera of C26 adenocarcinoma-bearing mice [19]. Increased amounts of very-low-density and low-density lipoproteins were detected along with decreased glucose levels [19]. Constantinou et al [20 •• ] applied 31 P MRS in vivo to detect changes in the muscle energy metabolism of cachectic mice inoculated with Lewis lung carcinoma cells.…”