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

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

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 3

Genotoxic HCC derives from hepatocytes.

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Genotoxic HCC derives from hepatocytes. mTom-mGFP Cre reporter mice (n =...
mTom-mGFP Cre reporter mice (n = 10) were infected with AAV8-Tbg-Cre to selectively label hepatocytes, followed by treatment with DEN and 20 injections of CCl4 for HCC induction. (A–C) Representative images and fluorescent images of livers from DEN+CCl4-treated mice (A) and H&E- and GFP-stained liver sections at low (B) and high (C) magnification, including an mTom-mGFP negative control. (D) Quantification of GFP-labeled hepatocytes and tumors (average of all mice, n = 10). (E) Typical HCC features were confirmed by collagen IV staining, increased Ki67 and glutamine synthetase levels, and altered Gp73 and β-catenin (β-Cat) staining. (F and G) HCC markers (F) and progenitor markers (G) were determined by qPCR. Scale bars: 1 cm (A); 1 mm (B); 50 μm (C); 300 μm (E). *P < 0.05, **P < 0.01, ***P < 0.01 by Kruskal-Wallis and Dunn’s post-hoc test.