Understanding the Clinical Significance of MUC5AC in Biliary Tract Cancers

Abstract

Biliary tract cancers (BTC) arise from biliary epithelium and include cholangiocarcinomas or CCA (including intrahepatic (ICC) and extrahepatic (ECC)) and gallbladder cancers (GBC). They often have poor outcomes owing to limited treatment options, advanced presentations, frequent recurrence, and poor response to available systemic therapy. Mucin 5AC (MUC5AC) is rarely expressed in normal biliary epithelium, but can be upregulated in tissues of benign biliary disease, premalignant conditions (e.g., biliary intraepithelial neoplasia), and BTCs. This mucin’s numerous glycoforms can be divided into less-glycosylated immature and heavily-glycosylated mature forms. Reported MUC5AC tissue expression in BTC varies widely, with some associations based on cancer location (e.g., perihilar vs. peripheral ICC). Study methods were variable regarding cancer subtypes, expression positivity thresholds, and MUC5AC glycoforms. MUC5AC can be detected in serum of BTC patients at high concentrations. The hesitancy in developing MUC5AC into a clinically useful biomarker in BTC management is due to variable evidence on the diagnostic and prognostic value. Concrete conclusions on tissue MUC5AC are difficult, but serum detection might be relevant for diagnosis and is associated with poor prognosis. Future studies are needed to further the understanding of the potential clinical value of MUC5AC in BTC, especially regarding predictive and therapeutic value.

Plasma Bile Acid Profiling and Modulation of Secreted Mucin 5AC in Cholangiocarcinoma

“…Although speculative, it can be hypothesised that the 230 kDa isoform observed in primary cholangiocytes may undergo additional post-translational modifications as the BAs injury progresses, possibly including heavier glycosylation that would slow its migration to an apparent size of approximately 270 kDa, which would explain why this band remains unchanged after treatment with BAs in HuH28 cell line. This hypothesis is supported by the recent observation that MUC5AC consists of numerous glycoforms including less-glycosylated immature isoforms and heavily glycosylated mature isoforms [ 45 ]. Further analysis with antibodies specific for both isoforms may be useful to demonstrate the appearance of aberrant glycosylation MUC5AC variants during malignant transformation.…”

“…If confirmed, such results may have important clinical implications. In fact, although it has been largely demonstrated that alterations of MUC5AC are associated with biliary carcinogenesis and that MUC5AC tissue expression might have predictive value in CCA treatment, the mechanism by which such alterations are induced remains to be explored [ 45 ]. Further studies are needed to confirm that the secretion of MUC5AC glycoprotein may be modulated by treatment of CCA cells with BAs and to determine whether induction of MUC5AC by BAs can increase the invasion potential of cells in vitro and their metastatic potential in vivo [ 46 ].…”

Efficacy of dual checkpoint inhibitors in a patient with a mixed hepatocellular cholangiocarcinoma

“…The benefit of adding an immuno-oncology (IO) agent to the conventional approach was demonstrated in the TOPAZ-1 study after the inclusion of durvalumab improved the objective response rate (ORR) and median overall survival (mOS, 12.8 months) when compared with chemotherapy alone plus placebo (11.5 months) 16. The outcomes of this study led to the inclusion of this drug in the standard of care 17. In the second-line setting, the ABC-06 trial remains as the landmark study.…”

Propionic Acid Restores Mucin Secretion in the Gastric Fundus in an Experimental Model of Type 2 Diabetes

“…Виявлено, що продукція нейтрального компоненту муцину зростала із збільшенням експресії MUC5AC, тоді як продукція кислого компоненту клітинами зменшувалася. Розуміння закономірностей секреції муцинів може допомогти у лікуванні та профілактиці захворювань, які пов'язані з травленням і зокрема всмоктуванням у шлунку пероральних засобів [19].…”