Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling.

Mice Animals Carcinoma, Hepatocellular / genetics Liver Neoplasms / genetics Cholangiocarcinoma Stem Cells Signal Transduction Carcinogenesis RNA Bile Duct Neoplasms Bile Ducts, Intrahepatic Forkhead Transcription Factors
Cancer stem cells Hepatocarcinogenesis Inflammation-induced cancer Oval cells

Journal

Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886

Informations de publication

Date de publication:
12 2022
Historique:
received: 16 06 2022
revised: 07 07 2022
accepted: 19 07 2022
pubmed: 22 8 2022
medline: 23 11 2022
entrez: 21 8 2022
Statut: ppublish

Résumé

Primary liver cancers include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA) and combined HCC-CCA tumors (cHCC-CCA). It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA or both types of tumors. To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor a yellow fluorescent protein (YFP) reporter gene driven by the Foxl1 promoter which is expressed specifically in progenitor cells. These mice (Mdr2-KO In this Mdr2-KO Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL-6, which derives in part from cells in senescence, plays an important role in this process via IL-6 trans-signaling. These findings could be applied to develop new therapeutic approaches for cHCC-CCA tumors. Combined hepatocellular carcinoma-cholangiocarcinoma is the third most prevalent type of primary liver cancer (i.e. a cancer that originates in the liver). Herein, we show that this type of cancer originates in stem cells in the liver and that it depends on inflammatory signaling. Specifically, we identify a cytokine called IL-6 that appears to be important in the development of these tumors. Our results could be used for the development of novel treatments for these aggressive tumors.

Sections du résumé

BACKGROUND & AIMS
Primary liver cancers include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA) and combined HCC-CCA tumors (cHCC-CCA). It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA or both types of tumors.
METHODS
To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor a yellow fluorescent protein (YFP) reporter gene driven by the Foxl1 promoter which is expressed specifically in progenitor cells. These mice (Mdr2-KO
RESULTS
In this Mdr2-KO
CONCLUSION
Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL-6, which derives in part from cells in senescence, plays an important role in this process via IL-6 trans-signaling. These findings could be applied to develop new therapeutic approaches for cHCC-CCA tumors.
LAY SUMMARY
Combined hepatocellular carcinoma-cholangiocarcinoma is the third most prevalent type of primary liver cancer (i.e. a cancer that originates in the liver). Herein, we show that this type of cancer originates in stem cells in the liver and that it depends on inflammatory signaling. Specifically, we identify a cytokine called IL-6 that appears to be important in the development of these tumors. Our results could be used for the development of novel treatments for these aggressive tumors.

Identifiants

DOI: 10.1016/j.jhep.2022.07.029 PMID: 35988690
pubmed: 35988690
pii: S0168-8278(22)02995-6
doi: 10.1016/j.jhep.2022.07.029
pii:
doi:

Substances chimiques

RNA 63231-63-0
Foxl1 protein, mouse 0
Forkhead Transcription Factors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1631-1641

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest S.R.-J. is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein, and he has stock ownership in CONARIS. Please refer to the accompanying ICMJE disclosure forms for further details.

Auteurs

Nofar Rosenberg (N)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Matthias Van Haele (M)

Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium; Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.

Tali Lanton (T)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Neta Brashi (N)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Zohar Bromberg (Z)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Hanan Adler (H)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Hilla Giladi (H)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Amnon Peled (A)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Daniel S Goldenberg (DS)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Jonathan H Axelrod (JH)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Alina Simerzin (A)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Chofit Chai (C)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Mor Paldor (M)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Auerlia Markezana (A)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Dayana Yaish (D)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Zohar Shemulian (Z)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Dvora Gross (D)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Shanny Barnoy (S)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Maytal Gefen (M)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Osher Amran (O)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Sofie Claerhout (S)

Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium.

Mirian Fernández-Vaquero (M)

Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

María García-Beccaria (M)

Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Danijela Heide (D)

Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Michal Shoshkes-Carmel (M)

Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Center for Translational Research, Philadelphia, USA.

Dirk Schmidt Arras (D)

Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany; Department of Biosciences, University of Salzburg, Salzburg, Austria.

Sharona Elgavish (S)

Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Yuval Nevo (Y)

Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Hadar Benyamini (H)

Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Janina E E Tirnitz-Parker (JEE)

Centre for Medical Research, University of Western Australia & Harry Perkins Institute of Medical Research, Crawley, Australia.

Aranzazu Sanchez (A)

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Spain.

Blanca Herrera (B)

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Spain.

Rifaat Safadi (R)

The Liver Institute, Hadassah Hebrew University Hospital, Jerusalem, Israel.

Klaus H Kaestner (KH)

Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Center for Translational Research, Philadelphia, USA.

Stefan Rose-John (S)

Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.

Tania Roskams (T)

Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium.

Mathias Heikenwalder (M)

Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; The M3 Research Institute, Rosenauer Weg 30, Medical Faculty Tuebingen (MFT), 72076 Tuebingen, Germany. Electronic address: m.heikenwaelder@dkfz-heidelberg.de.

Eithan Galun (E)

Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel. Electronic address: eithang@hadassah.org.il.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Eucaryotes › Animaux › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Carcinome hépatocellulaire › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Cholangiocarcinome › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Cellules › Cellules souches › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Carcinogenèse › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Maladies de l'appareil digestif › Tumeurs de l'appareil digestif › Tumeurs des voies biliaires › Tumeurs des canaux biliaires › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Système digestif › Foie › Conduits biliaires intrahépatiques › Combined hepatocellular-cholangiocarcinoma...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif hélice ailée › Facteurs de transcription Forkhead › Combined hepatocellular-cholangiocarcinoma...