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Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment
Xueru Mu, … , Isabelle A. Leclercq, Robert F. Schwabe
Xueru Mu, … , Isabelle A. Leclercq, Robert F. Schwabe
Published September 8, 2015
Citation Information: J Clin Invest. 2015;125(10):3891-3903. https://doi.org/10.1172/JCI77995.
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Research Article Oncology Article has an altmetric score of 4

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

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Abstract

In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19–, A6- and α-fetoprotein–positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.

Authors

Xueru Mu, Regina Español-Suñer, Ingmar Mederacke, Silvia Affò, Rita Manco, Christine Sempoux, Frédéric P. Lemaigre, Arlind Adili, Detian Yuan, Achim Weber, Kristian Unger, Mathias Heikenwälder, Isabelle A. Leclercq, Robert F. Schwabe

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Figure 5

HCCs are not derived from HSCs.

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HCCs are not derived from HSCs.
(A–D) Lrat-Cre Tg mice expressing the Zs...
(A–D) Lrat-Cre Tg mice expressing the ZsGreen Cre reporter (n = 4) were treated with DEN and 20 injections of CCl4 for HCC induction. Representative images and fluorescent images of livers from DEN+CCl4-treated mice (A) as well as H&E- and Hoechst-stained frozen liver sections at low and high magnification show green fluorescent HSCs but no green fluorescent tumor cells derived from HSCs (B). Typical HCC features were confirmed by collagen IV staining and increased Ki67 expression (C). ZsGreen-positive cells colocalized with the HSC marker desmin (D). (E–H) Mdr2KO mice expressing Lrat-Cre and the ZsGreen Cre reporter (n = 8) were sacrificed at 12 months of age. Representative images and fluorescent images of whole livers (E) as well as H&E- and Hoechst-stained frozen liver sections at low and high magnification show green fluorescent HSCs but no green fluorescent tumor cells derived from HSCs (F). Typical HCC features were confirmed by increased Ki67 expression and altered collagen IV staining (G). ZsGreen-positive cells colocalized with the HSC marker desmin (H). Scale bars: 5 mm (A and E); 500 μm (B, left panel and F, left panel); 50 μm (B, right panel and F, right panel); 500 μm (C and G); 50 μm (D and H).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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