High levels of modified ceramides are a defining feature of murine and human cancer cachexia

Abstract

Background Cancer cachexia (CCx) is a multifactorial energy-wasting syndrome reducing the efficiency of anti-cancer therapies, quality of life, and survival of cancer patients. In the past years, most studies focused on the identification of tumour and host-derived proteins contributing to CCx. However, there is still a lack of studies addressing the changes in bioactive lipids. The aim of this study was to identify specific lipid species as a hallmark of CCx by performing a broad range lipid analysis of plasma from well-established CCx mouse models as well as cachectic and weight stable cancer patients. Methods Plasma from non-cachectic (PBS-injected mice, NC26 tumour-bearing mice), pre-cachectic and cachectic mice (C26 and LLC tumour-bearing mice, Apc Min/+ mutant mice), and plasma from weight stable and cachectic patients with gastrointestinal cancer, were analysed using the Lipidyzer ™ platform. In total, 13 lipid classes and more than 1100 lipid species, including sphingolipids, neutral and polar glycerolipids, were covered by the analysis. Correlation analysis between specific lipid species and readouts of CCx were performed. Lipidomics data were confirmed by gene expression analysis of metabolic organs to analyse enzymes involved in sphingolipid synthesis and degradation. Results A decrease in several lysophosphatidylcholine (LPC) species and an increase in numerous sphingolipids including sphingomyelins (SMs), ceramides (CERs), hexosyl-ceramides (HCERs) and lactosyl-ceramides (LCERs), were mutual features of CCx in both mice and cancer patients. Notably, sphingolipid levels gradually increased during cachexia development. Key enzymes involved in ceramide synthesis were elevated in liver but not in adipose, muscle, or tumour tissues, suggesting that ceramide turnover in the liver is a major contributor to elevated sphingolipid levels in

Exercise—A Panacea of Metabolic Dysregulation in Cancer: Physiological and Molecular Insights

“…When stratifying the results between patients with and without cachexia, lipase activities were significantly higher in patients with cancer cachexia compared with patients without cachexia [ 66 ]. Accordingly, high levels of circulating sphingolipids was observed in murine and human cancer cachexia [ 71 ]. Hyperlipidemia also seems to reach the muscle, as the number of intramyocellular lipid droplets was increased in patients with cancer and positively correlates with involuntary weight-loss [ 72 ].…”

Obesity-Related Changes in Human Plasma Lipidome Determined by the Lipidyzer Platform

“…All statistical analyses were performed with the IBM SPSS software (version 26, IBM Company, Armonk, NY, USA). For better comparison with the results of previous studies (Bowden et al, 2017; Sales et al, 2016), the lipid concentrations obtained in nmol/gram plasma were transformed to µmol/L assuming that 1 g of plasma is equal to 1 mL of plasma as described by Morigny et al [ 22 ]. The concentrations of each lipid species including FAs were adjusted by blank correction.…”

Biomarkers for Cancer Cachexia: A Mini Review

“…In a study investigating lipid profiles of cancer cachexia, increased circulating levels of sphingolipids were found in different preclinical models and cachectic patients with gastrointestinal cancers [ 13 ]. Specifically, circulating levels of hexosyl-ceramides (HCERs) and lactosyl-ceramides (LCERs) were significantly higher in cachectic patients compared with weight stable patients [ 13 ]. Although this study was limited by the small cohort of patients (20 cachectic and 19 weight stable cancer patients), the finding was promising, as it shows a consistency between preclinical models and clinical patients.…”

“…A biomarker-based evaluation system for cancer cachexia could solve these issues as biomarkers are a more objective and reliable diagnostic tool than functional assessment. Several potential biomarkers have so far been identified including some cachexia-inducing factors [ 9 , 10 ], pro-inflammatory cytokines [ 11 , 12 ], lipids [ 13 ], protein and fat degradation products [ 14 ], and microRNAs [ 15 ]. Nevertheless, none of these candidates have been widely validated and accepted as clinical diagnostic standards for cancer cachexia.…”