دورية أكاديمية
Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling.
| العنوان: | Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling. |
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| المؤلفون: | Rosenberg N; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., 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., Lanton T; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Brashi N; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Bromberg Z; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Adler H; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Giladi H; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Peled A; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Goldenberg DS; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Axelrod JH; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Simerzin A; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Chai C; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Paldor M; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Markezana A; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Yaish D; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Shemulian Z; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Gross D; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Barnoy S; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Gefen M; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Amran O; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel., Claerhout S; Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium., Fernández-Vaquero M; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., García-Beccaria M; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Heide D; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., 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., Schmidt Arras D; Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany; Department of Biosciences, University of Salzburg, Salzburg, Austria., Elgavish S; Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel., Nevo Y; Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel., Benyamini H; Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel., Tirnitz-Parker JEE; Centre for Medical Research, University of Western Australia & Harry Perkins Institute of Medical Research, Crawley, Australia., Sanchez A; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Spain., Herrera B; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Spain., Safadi R; The Liver Institute, Hadassah Hebrew University Hospital, Jerusalem, Israel., 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., Rose-John S; Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany., Roskams T; Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium., 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., Galun E; Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel. Electronic address: eithang@hadassah.org.il. |
| المصدر: | Journal of hepatology [J Hepatol] 2022 Dec; Vol. 77 (6), pp. 1631-1641. Date of Electronic Publication: 2022 Aug 18. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2001- : Amsterdam : Elsevier Original Publication: Copehnagen : Munksgaard International Publishers, [c1984- |
| مواضيع طبية MeSH: | Carcinoma, Hepatocellular*/genetics , Liver Neoplasms*/genetics , Cholangiocarcinoma* , Bile Duct Neoplasms*, Mice ; Animals ; Stem Cells ; Signal Transduction ; Carcinogenesis ; RNA ; Bile Ducts, Intrahepatic ; Forkhead Transcription Factors |
| مستخلص: | 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 Foxl1-CRE;RosaYFP ) develop chronic inflammation and HCCs by the age of 14-16 months, followed by cHCC-CCA tumors at the age of 18 months. Results: In this Mdr2-KO Foxl1-CRE;RosaYFP mouse model, liver progenitor cells are the source of cHCC-CCA tumors, but not the source of HCC. Ablating the progenitors, caused reduction of cHCC-CCA tumors but did not affect HCCs. RNA-sequencing revealed enrichment of the IL-6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. Single-cell RNA-sequencing (scRNA-seq) analysis revealed that IL-6 is expressed by immune and parenchymal cells during senescence, and that IL-6 is part of the senescence-associated secretory phenotype. Administration of an anti-IL-6 antibody to Mdr2-KO Foxl1-CRE;RosaYFP mice inhibited the development of cHCC-CCA tumors. Blocking IL-6 trans-signaling led to a decrease in the number and size of cHCC-CCA tumors, indicating their dependence on this pathway. Furthermore, the administration of a senolytic agent inhibited IL-6 and the development of cHCC-CCA tumors. 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. Competing Interests: 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. (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.) |
| التعليقات: | Comment in: J Hepatol. 2022 Dec;77(6):1479-1481. (PMID: 36150576) |
| فهرسة مساهمة: | Keywords: Cancer stem cells; Hepatocarcinogenesis; Inflammation-induced cancer; Oval cells |
| المشرفين على المادة: | 63231-63-0 (RNA) 0 (Foxl1 protein, mouse) 0 (Forkhead Transcription Factors) |
| تواريخ الأحداث: | Date Created: 20220821 Date Completed: 20221122 Latest Revision: 20221128 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.jhep.2022.07.029 |
| PMID: | 35988690 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1600-0641 |
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| DOI: | 10.1016/j.jhep.2022.07.029 |