Changing Metabolic Patterns along the Colorectal Adenoma–Carcinoma Sequence

Abstract

Colorectal cancer (CRC) is a major public health burden and one of the leading causes of cancer-related deaths worldwide. Screening programs facilitate early diagnosis and can help to reduce poor outcomes. Serum metabolomics can extract vital molecular information that may increase the sensitivity and specificity of colonoscopy in combination with histopathological examination. The present study identifies serum metabolite patterns of treatment-naïve patients, diagnosed with either advanced adenoma (AA) or CRC in colonoscopy screenings, in the framework of the SAKKOPI (Salzburg Colon Cancer Prevention Initiative) program. We used a targeted flow injection analysis and liquid chromatography-tandem mass spectrometry metabolomics approach (FIA- and LC-MS/MS) to characterise the serum metabolomes of an initial screening cohort and two validation cohorts (in total 66 CRC, 76 AA and 93 controls). The lipidome was significantly perturbed, with a proportion of lipid species being downregulated in CRC patients, as compared to AA and controls. The predominant alterations observed were in the levels of lyso-lipids, glycerophosphocholines and acylcarnitines, but additionally, variations in the quantity of hydroxylated sphingolipids could be detected. Changed amino acid metabolism was restricted mainly to metabolites of the arginine/dimethylarginine/NO synthase pathway. The identified metabolic divergences observed in CRC set the foundation for mechanistic studies to characterise biochemical pathways that become deregulated during progression through the adenoma to carcinoma sequence and highlight the key importance of lipid metabolites. Biomarkers related to these pathways could improve the sensitivity and specificity of diagnosis, as well as the monitoring of therapies.

Lipid Metabolism Interplay in CRC—An Update

“…LC-MS-based serum profiles showed saturated TAG as the main perturbed lipids in CRC progression and the authors pointed towards LD accumulation as the origin [ 102 ]. Another group observed decreased levels of lyso-lipids, glycophosphocholines and acylcarnitines serum concentrations in CRC patients [ 103 ]. Very recently, Ecker et al additionally identified a robust TG lipidomic tissue signature that could discriminate patients and was proposed as prognostic identifier.…”

Salivary metabolomics with machine learning for colorectal cancer detection

“…14 In addition, holistic changes in the metabolic pathways have been reported, including amino acid, pentose phosphate, urea cycle, polyamine, and nucleotide pathways. [15][16][17] Therefore, the metabolites in biofluids including blood and saliva that reflect these metabolic aberrances associated with CRC have been analyzed to establish a novel set of biomarkers. [18][19][20][21][22][23][24] Saliva is an ideal biofluid that enables various disease detections.…”

“…Glutamine is used as a carbon source alternative to glucose via the TCA in proliferating tumor cells to synthesize purines and pyrimidines 14 . In addition, holistic changes in the metabolic pathways have been reported, including amino acid, pentose phosphate, urea cycle, polyamine, and nucleotide pathways 15–17 . Therefore, the metabolites in biofluids including blood and saliva that reflect these metabolic aberrances associated with CRC have been analyzed to establish a novel set of biomarkers 18–24 …”

UHPLC-HRMS–based serum lipisdomics reveals novel biomarkers to assist in the discrimination between colorectal adenoma and cancer

“…Lipid species are widely distributed and important endogenous substances in vivo that have been demonstrated to be involved in the occurrence and development of various tumors ( 17 , 18 ). Recent studies have reported that perturbation of lipid metabolism is closely related to the progression of CRC ( 19 , 20 ). The lipid metabolic pathways in CRC cells are affected, including fatty acid synthesis, desaturation, elongation, and mitochondrial oxidation ( 21 ).…”