Tumor ratio of unsaturated to saturated sulfatide species is associated with disease-free survival in intrahepatic cholangiocarcinoma

Abstract

Purpose Cholangiocarcinoma (CCA) is a malignancy arising from the bile duct epithelium and has a poor outcome. Sulfatides are lipid components of lipid rafts, and are implicated in several cancer types. In the liver, sulfatides are specifically present in the bile ducts. Here, sulfatide abundance and composition were analyzed using mass spectrometry imaging in intrahepatic CCA (iCCA) tumor tissue, and correlated with tumor biology and clinical outcomes. Methods Sulfatides were analyzed in iCCA (n = 17), hepatocellular carcinoma (HCC, n = 10) and colorectal liver metastasis (CRLM, n = 10) tumor samples, as well as tumor-distal samples (control, n = 16) using mass spectrometry imaging. Levels of sulfatides as well as the relative amount in structural classes were compared between groups, and were correlated with clinical outcomes for iCCA patients. Results Sulfatide localization was limited to the respective tumor areas and the bile ducts. Sulfatide abundance was similar in iCCA and control tissue, while intensities were notably higher in CRLM in comparison with control (18-fold, P < 0.05) and HCC tissue (47-fold, P < 0.001). Considerable variation in sulfatide abundance was observed in iCCA tumors. A high ratio of unsaturated to saturated sulfatides was associated with reduced disease-free survival (10 vs. 20 months) in iCCA. The sulfatide pattern in HCC deviated from the other groups, with a higher relative abundance of odd- versus even-chain sulfatides. Conclusion Sulfatides were found in tumor tissue of patients with iCCA, with sulfatide abundance per pixel being similar to bile ducts. In this explorative study, sulfatide abundance was not related to overall survival of iCCA patients. A high ratio of unsaturated to saturated sulfatides was associated with earlier tumor recurrence in patients with iCCA.

Prognostic potential of lipid profiling in cancer patients: a systematic review of mass spectrometry-based studies

“…The number of studies reported for each cancer type is as follows (Fig. 4 a): there were six studies (16%) each on colorectal [ 24 – 29 ] and prostate cancer [ 30 – 35 ], five (13%) on breast cancer [ 36 – 40 ], three (8%) each on lung [ 41 – 43 ] and ovarian cancer [ 44 – 46 ], two (5%) on bladder cancer [ 47 , 48 ], intrahepatic cholangiocarcinoma [ 49 , 50 ], pancreatic cancer [ 51 , 52 ], and renal cell carcinoma [ 53 , 54 ], one (3%) each from cervical cancer [ 55 ], chordoma [ 56 ], endometrial cancer [ 57 ], liver cancer [ 58 ], malignant mesothelioma [ 59 ], nasopharyngeal carcinoma [ 60 ], and oral cancer [ 61 ].…”

“…The number of studies reported for each country is as follows (Fig. 4 b): 10 studies (26%) were reported from China [ 24 , 26 , 28 , 45 , 46 , 50 , 52 , 55 , 59 , 60 ], eight (21%) from Japan [ 31 , 37 – 39 , 41 – 43 , 53 ], four (11%) from the USA [ 30 , 33 , 47 , 48 ], two (5%) each from Australia [ 32 , 34 ], Brazil [ 29 , 61 ], and Germany [ 25 , 40 ], one (3%) each from Argentina [ 54 ], Canada [ 57 ], Czech [ 51 ], Finland [ 44 ], Italy [ 56 ], Netherlands [ 49 ], Portugal [ 36 ], Romania [ 27 ], Singapore [ 58 ], and Spain [ 35 ].…”

“…In two cases of serum and one urine, extracellular vesicle (EV) was used as the measurement materials [ 35 , 40 , 52 ]. For the analysis of tissue samples, the most commonly used analysis platform was liquid chromatography–tandem mass spectrometry (LC-MS), accounting for 12 cases (60%) [ 30 , 31 , 38 , 41 – 43 , 47 , 48 , 56 , 58 , 60 , 61 ], followed by imaging mass spectrometry (IMS) [ 37 , 49 , 50 , 53 ] and other methods [ 24 , 25 , 36 , 47 ], each with four cases (20%). In the analysis of serum samples, LC-MS was predominantly used in 17 cases (85%) [ 26 – 28 , 32 – 34 , 39 , 44 – 46 , 52 , 54 , 55 , 57 – 59 , 61 ], with other methods being used in three cases (15%) [ 29 , 40 , 51 ].…”

“…In the studies, the molecular identification methods used were predominantly software-based, accounting for 19 cases (49%) [ 25 , 26 , 28 , 30 , 33 , 40 , 44 – 48 , 51 , 52 , 54 – 57 , 59 , 61 ], followed by databases in eight cases (21%) [ 24 , 27 , 29 , 33 , 35 , 50 , 53 , 58 ]. Direct verification of raw-tandem MS (MS/MS) data and the use of radioisotope-labeled standards were each employed in eight (21%) [ 31 , 32 , 34 , 37 , 41 – 43 , 49 ] and two cases (5%) [ 38 , 39 ]. There were also two cases (5%) [ 36 , 60 ] where the details were not specified in the text.…”

Reduced sulfatide content in deferoxamine-induced senescent HepG2 cells

“…Levels of sulfatides are generally elevated in colorectal, ovarian, or renal carcinoma ( Jirásko et al, 2022 ) and intrahepatic cholangiocarcinoma ( Huizing et al, 2023 ). Sulfatides are often elevated in hepatocellular carcinma (HCC) ( Takahashi and Suzuki, 2012 ), and previous studies have shown that sulfatides are promoters of cell adhesion and metastasis in HCC ( Wang et al, 2016 ).…”