Linoleic acid pathway disturbance contributing to potential cancerization of intrahepatic bile duct stones into intrahepatic cholangiocarcinoma

Abstract

Background Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy with poor prognosis. Intrahepatic bile duct stone (IBDS) is one of the key causes to ICC occurrence and can increase morbidity rate of ICC about forty times. However, the specific carcinogenesis of IBDS is still far from clarified. Insight into the metabolic phenotype difference between IBDS and ICC can provide potential mechanisms and therapeutic targets, which is expected to inhibit the carcinogenesis of IBDS and improve the prognosis of ICC. Methods A total of 34 participants including 25 ICC patients and 9 IBDS patients were recruited. Baseline information inclusive of liver function indicators, tumor biomarkers, surgery condition and constitution parameters etc. from patients were recorded. ICC and IBDS pathological tissues, as well as ICC para-carcinoma tissues, were collected for GC–MS based metabolomics experiments. Multivariate analysis was performed to find differentially expressed metabolites and differentially enriched metabolic pathways. Spearman correlation analysis was then used to construct correlation network between key metabolite and baseline information of patients. Results The IBDS tissue and para-carcinoma tissue have blurred metabolic phenotypic differences, but both of them essentially distinguished from carcinoma tissue of ICC. Metabolic differences between IBDS and ICC were enriched in linoleic acid metabolism pathway, and the level of 9,12-octadecadienoic acid in IBDS tissues was almost two times higher than in ICC pathological tissues. The correlation between 9,12-octadecadienoic acid level and baseline information of patients demonstrated that 9,12-octadecadienoic acid level in pathological tissue was negative correlation with gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) level in peripheral blood. These two indicators were all cancerization marker for hepatic carcinoma and disease characteristic of IBDS. Conclusion Long-term monitoring of metabolites from linoleic acid metabolism pathway and protein indicators of liver function in IBDS patients has important guiding significance for the monitoring of IBDS carcinogenesis. Meanwhile, further insight into the causal relationship between linoleic acid pathway disturbance and changes in liver function can provide important therapeutic targets for both IBDS and ICC.

Long-term outcomes of anatomic vs. non-anatomic resection in intrahepatic cholangiocarcinoma with hepatolithiasis: A multicenter retrospective study

“…As for those with HICC, their prognosis was poorer than patients with ICC without hepatolithiasis ( 16 , 17 ). Hepatolithiasis frequently results in the development of atypical epithelium, oncogene activation, and inflammation, leading to the high occurrence of periductal invasion and LNM, which leads to a poor prognosis ( 18 , 19 ). However, the early symptoms of HICC are not typical and can be easily concealed by intrahepatic bile duct stones and cholangitis.…”

Interplay between the Human Microbiome and Biliary Tract Cancer: Implications for Pathogenesis and Therapy

“…Their findings emphasized that the metabolic disparities between IBDS and ICC mainly revolve around linoleic acid metabolic pathways. Perturbations in the linoleic acid pathway might contribute to the potential malignant transformation of intrahepatic bile duct stones into ICC [83]. Chai et al discovered that results from both in vitro and in vivo experiments strongly support the idea that P. fungorum demonstrates anti-tumor activity by modulating alanine, aspartate, and glutamate metabolism [23].…”

Interplay Between the Human Microbiome and Biliary Tract Cancer: Implications for Pathogenesis and Therapy

“…Their findings emphasized that the metabolic disparities between IBDS and ICC mainly revolve around linoleic acid metabolic pathways. Perturbations in the linoleic acid pathway might contribute to the potential malignant transformation of intrahepatic bile duct stones into ICC [82]. Chai et al discovered that results from both in vitro and in vivo experiments strongly support the idea that P. fungorum demonstrates antitumor activity by modulating alanine, aspartate, and glutamate metabolism [23].…”