Ceramides Profile Identifies Patients with More Advanced Stages of Colorectal Cancer

Abstract

Much attention is paid to different sphingolipid pathways because of their possible use in diagnostics and treatment. However, the activity status and significance of ceramide pathways in colorectal cancer are still unclear. We analyzed colorectal cancer patients to evaluate sphingolipid profiles in the blood, colorectal cancer (CRC) tissues, and healthy surrounding colorectal tissues of the same patient, simultaneously, using liquid chromatography coupled with triple quadrupole mass spectrometry. Furthermore, we measured protein expression of de novo ceramide synthesis enzymes and mitochondrial markers in tissues using western blot. We confirmed the different sphingolipid contents in colorectal cancer tissue compared to healthy surrounding tissues. Furthermore, we showed changed amounts of several ceramides in more advanced colorectal cancer tissue and found a prominently higher circulating level of several of them. Moreover, we observed a relationship between the amounts of some ceramide species in colorectal cancer tissue and plasma depending on the stage of colorectal cancer according to TNM (tumors, nodes, metastasis) classification. We think that the combined measurement of several ceramide concentrations in plasma can help distinguish early-stage lesions from advanced colorectal cancer and can help produce a screening test to detect early colorectal cancer.

Alterations in complex lipids in tumor tissue of patients with colorectal cancer

“…In current study, the difference in total Cer amounts between tumor and tumor adjacent tissue (Fig. 1) are in agreement with previous reports of elevated Cer synthases expression levels [54], as well as total Cer content in CRC tissues [29,53].…”

“…It has been shown that they regulate ion channels, which may constitute the mechanism underlying the regulation of cell proliferation [52]. Likewise, the exact nature of sphingolipid metabolism in carcinogenic processes is not yet clear, but seems to be dependent on acyl-chain composition [53]. In current study, the difference in total Cer amounts between tumor and tumor adjacent tissue (Fig.…”

“…The advantage of this study was also using the matched tumor adjacent, micro and macroscopically normal colon mucosa and tumor samples from the same patients. Although the issue of field cancerization has been raised before [68] the paired tissue samples seem to be the most suitable controls, given the apparent heterogeneity of tissue samples [29,53].…”

The key role of sphingolipid metabolism in cancer: New therapeutic targets, diagnostic and prognostic values, and anti-tumor immunotherapy resistance

“…Interestingly, an investigation on colorectal cancer (CRC) tissue has suggested that CRC shows increased amounts of S1P, Sph, and C14-Cer and markedly reduced amounts of C18-Cer and C20-Cer. The circulating contents of C16:0-Cer, C18:1-Cer, C20-Cer, and C24:1-Cer in more advanced CRC were higher than those in early lesions ( 32 ). These results suggest that early lesions can be distinguished from advanced CRC through the combined determination of the plasma concentrations of several ceramides.…”

Diagnostic value of serum sphingolipids in patients with colorectal cancer

“…Sphingolipids such as ceramide, sphingosine, sphingosine-1-phosphate (S1P), and ceramide-1-phosphate (C1P) play important roles in cell signaling events, including apoptosis, differentiation, regulation of receptor kinase and phospholipase activities. 11 Although the implication and function of sphingolipids in cell signaling has been highly controversial, accumulating evidence suggests that CRC in different stages exhibits alterations in sphingolipids and their metabolizing enzymes, either in the serum or the tumor, 12–14 and several studies have found that dietary sphingolipids or the gut microbiome influence CRC carcinogenesis via alterations in sphingolipids. 15…”