Ceramide present in cholangiocarcinoma-derived extracellular vesicle induces a pro-inflammatory state in monocytes

Author:

Oliviero Barbara,Dei Cas Michele,Zulueta Aida,Maiello Roberta,Villa Alessandro,Martinelli Carla,Del Favero Elena,Falleni Monica,Montavoci Linda,Varchetta Stefania,Mele Dalila,Donadon Matteo,Soldani Cristiana,Franceschini Barbara,Maestri Marcello,Piccolo Gaetano,Barabino Matteo,Bianchi Paolo Pietro,Banales Jesus M.,Mantovani Stefania,Mondelli Mario U.,Caretti Anna

Abstract

AbstractCholangiocarcinoma (CCA) is a rare cancer characterized by a global increasing incidence. Extracellular vesicles (EV) contribute to many of the hallmarks of cancer through transfer of their cargo molecules. The sphingolipid (SPL) profile of intrahepatic CCA (iCCA)-derived EVs was characterized by liquid chromatography-tandem mass spectrometry analysis. The effect of iCCA-derived EVs as mediators of inflammation was assessed on monocytes by flow cytometry. iCCA-derived EVs showed downregulation of all SPL species. Of note, poorly-differentiated iCCA-derived EVs showed a higher ceramide and dihydroceramide content compared with moderately-differentiated iCCA-derived EVs. Of note, higher dihydroceramide content was associated with vascular invasion. Cancer-derived EVs induced the release of pro-inflammatory cytokines in monocytes. Inhibition of synthesis of ceramide with Myriocin, a specific inhibitor of the serine palmitoyl transferase, reduced the pro-inflammatory activity of iCCA-derived EVs, demonstrating a role for ceramide as mediator of inflammation in iCCA. In conclusion, iCCA-derived EVs may promote iCCA progression by exporting the excess of pro-apoptotic and pro-inflammatory ceramides.

Funder

Italian Ministry of Health, Ricerca Corrente

University of Milan, Italy, Piano di Sostegno alla Ricerca 2020

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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