Different iron-handling in inflamed small and large cholangiocytes and in small and large-duct type intrahepatic cholangiocarcinoma

Romina Mancinelli; Antimo Cutone; Luigi Rosa; Maria Stefania Lepanto; Paolo Onori; Luigi Pannarale; Antonio Franchitto; Eugenio Gaudio; Piera Valenti

doi:10.4081/ejh.2020.3156

https://doi.org/10.4081/ejh.2020.3156

Authors

Romina Mancinelli | romina.mancinelli@uniroma1.it Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Italy. https://orcid.org/0000-0003-2040-0581
Antimo Cutone Department of Biosciences and Territory, University of Molise, Pesche (IS), Italy. https://orcid.org/0000-0002-7492-8616
Luigi Rosa Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy. https://orcid.org/0000-0002-1252-6080
Maria Stefania Lepanto Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy.
Paolo Onori Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome , Italy. https://orcid.org/0000-0002-7195-3760
Luigi Pannarale Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome , Italy. https://orcid.org/0000-0002-3505-5066
Antonio Franchitto Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome; Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy.
Eugenio Gaudio Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome , Italy.
Piera Valenti Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy. https://orcid.org/0000-0002-4354-3190

Abstract

Cholangiocarcinoma (CCA) represents the second most common primary hepatic malignancy and originates from the neoplastic transformation of the biliary cells. The intrahepatic subtype includes two morpho-molecular forms: large-duct type intrahepatic CCA (iCCA) and small-duct type iCCA. Iron is fundamental for the cellular processes, contributing in tumor development and progression. The aim of this study was to evaluate iron uptake, storage, and efflux proteins in both lipopolysaccharide-inflamed small and large cholangiocytes as well as in different iCCA subtypes. Our results show that, despite an increase in interleukin-6 production by both small and large cholangiocytes, ferroportin (Fpn) was decreased only in small cholangiocytes, whereas transferrin receptor-1 (TfR1) and ferritin (Ftn) did not show any change. Differently from in vitro models, Fpn expression was increased in malignant cholangiocytes of small-duct type iCCA in comparison to large-duct type iCCA and peritumoral tissues. TfR1, Ftn and hepcidin were enhanced, even if at different extent, in both malignant cholangiocytes in comparison to the surrounding samples. Lactoferrin was higher in large-duct type iCCA in respect to small-duct type iCCA and peritumoral tissues. These findings show a different iron handling by inflamed small and large cholangiocytes, and small and large-duct type iCCA. The difference in iron homeostasis by the iCCA subtypes may have implications for the tumor management.