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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Detailing the ultrastructure’s increase of prion protein in pancreatic adenocarcinoma
Matteo Bianchini, Maria Anita Giambelluca, Maria Concetta Scavuzzo, Gregorio Di Franco, Simone Guadagni, Matteo Palmeri, Niccolò Furbetta, Desirée Gianardi, Niccola Funel, Claudio Ricci, Raffaele Gaeta, Luca Emanuele Pollina, Alfredo Falcone, Caterina Vivaldi, Giulio Di Candio, Francesca Biagioni, Carla Letizia Busceti, Luca Morelli, Francesco Fornai
Matteo Bianchini, Gregorio Di Franco, Simone Guadagni, Matteo Palmeri, Niccolò Furbetta, Desirée Gianardi, Giulio Di Candio, Luca Morelli, General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
Maria Anita Giambelluca, Maria Concetta Scavuzzo, Francesco Fornai, Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
Niccola Funel, Claudio Ricci, Raffaele Gaeta, Luca Emanuele Pollina, Division of Surgical Pathology, Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa 56124, Italy
Alfredo Falcone, Caterina Vivaldi, Division of Medical Oncology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
Francesca Biagioni, Carla Letizia Busceti, Francesco Fornai, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli 86077, Italy
Luca Morelli, EndoCAS (Center for Computer Assisted Surgery), University of Pisa, Pisa 56124, Italy
Author contributions: Bianchini M and Giambelluca MA contributed equally to this work; Morelli L and Fornai F contributed equally to this work; Bianchini M, Giambelluca MA, Scavuzzo MC, Morelli L and Fornai F studied the conception and design; Bianchini M, Giambelluca MA, Scavuzzo MC, Di Franco G, Guadagni S, Palmeri M, Furbetta N, Gianardi D, Funel N, Ricci C, Gaeta R, Pollina LE, Falcone A, Vivaldi C and Di Candio G contributed to data acquisition; Morelli L and Fornai F are responsible for data analysis and interpretation, and revised the manuscript critically; Bianchini M, Giambelluca MA, Scavuzzo MC, Di Franco G, Guadagni S, Palmeri M, Furbetta N, Gianardi D, Funel N, Pollina LE, Falcone A, Vivaldi C, Di Candio C, Biagioni F and Busceti CL drafted the manuscript; all authors approved the final manuscript.
Supported by Tizzi Foundation and Arpa Foundation (www.fondazionearpa.it).
Institutional review board statement: The study was approved by Ethics committee of “Area Vasta Nord Ovest (CEAVNO)”.
Informed consent statement: All patients signed an informed consent to authorize the scientific use of the collected data.
Conflict-of-interest statement: The authors declare that they do not have any conflict of interest.
Data sharing statement: No additional data available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Luca Morelli, MD, Professor, General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, Pisa 56124, Italy. luca.morelli@unipi.it
Received: April 27, 2021
Peer-review started: April 27, 2021
First decision: June 13, 2021
Revised: June 14, 2021
Accepted: October 25, 2021
Article in press: October 25, 2021
Published online: November 14, 2021
ARTICLE HIGHLIGHTS
Research background
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers, but its molecular basis is still poorly understood. Among the several new targets for the comprehension of its biology, cellular Prion protein (PrPc) deserves particular mention, since it seems to be involved also in tumorigenesis.
Research motivation
Recent evidences have shown a relationship between PrPc expression and PDAC, with a possible role of this protein in the molecular basis of PDAC aggressiveness itself.
Research objectives
The present study aimed to further analyze the occurrence of PrPc within PDAC tissues, by investigating the specific compartmentalization of PrPc within PDAC cells, which is a fundamental aspect in order to provide a significant advancement in understanding the biology of disease. Moreover, we aimed to correlate the presence of PrPc with clinical data in order to find an association with patients’ prognosis.
Research methods
Samples from pancreatic tissues of 45 patients treated with pancreatic resection PDAC at a single institution were collected. Immune-gold stoichiometry within specific cell compartments was analyzed with electron microscopy in order to elucidate the subcellular compartmentalization of PrPc within PDAC cells. Western blotting was used to detect, quantify and compare the expression of PrPc in PDAC and control tissues, such as those of non-affected neighboring pancreatic tissue of the same patient. Data from western blot analysis where also used to perform a correlation with prognostic data from patients’ follow-up.
Research results
Immune-electron microscopy highlighted an increased PrPc expression in PDAC ductal cells of all patients and allowed to detect a peculiar compartmentalization of PrPc within tumor cells, with a specific increase of PrPc in the nucleus. Furthermore, semi-quantitative analysis by using Western blotting, showed that PrPc increased almost three-fold in tumor pancreatic tissue compared with healthy pancreatic regions, with a significantly higher expression of PrPc in patients with disease recurrence at 12 mo after radical surgery, also in the subgroup of patients treated with adjuvant CT, thus revealing a possible higher chemoresistance.
Research conclusions
Our study provides evidence for a correlation between PrPc expression in PDAC and a worse biological behavior, with a higher recurrence rate and chemo-resistance. Moreover, it provides for the first-time the evidence of a peculiar subcellular compartmentalization of PrPc itself within PDAC cells.
Research perspectives
PrPc could be a molecular marker associated to PDAC aggressiveness and ominous prognosis. Its nuclear compartmentalization suggests the activation of specific, but still unknown, molecular pathways involved in the biology of the disease and further studies in this sense are necessary, since specific therapeutic agents designed to target PrPc metabolism should be able to reduce a pathological cell growth and to revert chemo-resistance.
