Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling
Open accessAbstract
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 c…
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Blocking IL-6 trans-signaling using soluble gp130, clearing senescent cells using a senolytic agent, or depleting hepatic progenitor cells results in significant reduction of hepatocellular-cholangiocarcinoma tumors.
“Blocking IL-6 trans-signaling using soluble gp130 or clearing senescent cells using a senolytic agent, as well as the depletion of hepatic progenitor cells, result in a significant reduction of hepatocellular-cholangiocarcinoma tumors [44, 45].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [44]
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Targeting IL-6 trans-signalling: past, present and future prospects
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Self-citationThe double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases
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“Blocking IL-6 trans -signaling using soluble gp130 or clearing senescent cells using a senolytic agent, as well as the depletion of hepatic progenitor cells, result in a significant reduction of hepatocellular-cholangiocarci-noma tumors [44, 45].”
BackgroundCholangiokines: undervalued modulators in the hepatic microenvironment
Cai, X., Tacke, F., Guillot, A., & Liu, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1192840 · Cited by 40 · see citing works
- Authors
- Rosenberg, N., Van Haele, M., Lanton, T., Brashi, N., Bromberg, Z., Adler, H., Giladi, H., Peled, A., Goldenberg, D. S., Axelrod, J. H., Simerzin, A., Chai, C., Paldor, M., Markezana, A., Yaish, D., Shemulian, Z., Gross, D., Barnoy, S., Gefen, M., Amran, O., Claerhout, S., Fernández-Vaquero, M., García-Beccaria, M., Heide, D., Shoshkes-Carmel, M., Schmidt Arras, D., Elgavish, S., Nevo, Y., Benyamini, H., Tirnitz-Parker, J. E. E., Sanchez, A., Herrera, B., Safadi, R., Kaestner, K. H., Rose-John, S., Roskams, T., Heikenwalder, M., & Galun, E.
- Affiliations
- Hadassah Medical Center (IL)
- KU Leuven (BE)
- German Cancer Research Center (DE)
- University of Pennsylvania (US)
- Hebrew University of Jerusalem (IL)
- Universidad Complutense de Madrid (ES)
- Corresponding author
- Galun, Eithan
- ORCID
- Peled, Amnon
- Goldenberg, Daniel S.
- Axelrod, Jonathan H.
- Simerzin, Alina
- Paldor, Mor
- Markezana, Auerlia
- Claerhout, Sofie
- Fernández-Vaquero, Mirian
- García-Beccaria, María
- Heide, Danijela
- Shoshkes-Carmel, Michal
- Schmidt Arras, Dirk
- Elgavish, Sharona
- Nevo, Yuval
- Tirnitz-Parker, Janina E.E.
- Herrera, Blanca
- Safadi, Rifaat
- Kaestner, Klaus H.
- Rose-John, Stefan
- Roskams, Tania
- Galun, Eithan
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 77
- Issue
- 6
- Pages
- 1631-1641
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W4292416121
- Cited by
- 72
- References
- 9
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 21 · 2023: 18 · 2022: 1
- FWCI
- 8.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Hepatology (acceptedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Keywords
- OMA, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver progenitor cells, hepatocarcinogenesis, senescence-associated secretory phenotype, IL-6 trans-signaling, interleukin-6, senolytics, Mdr2 knockout mice, chronic liver inflammation, tumor origin, anti-IL-6 antibody
- MeSH terms
- Animals, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Carcinoma, Hepatocellular, Liver Neoplasms, RNA, Stem Cells, Signal Transduction, Cholangiocarcinoma, Mice, Forkhead Transcription Factors, Carcinogenesis
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