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 2

HCC does not derive from the LPC/biliary compartment in the DEN+CCl4 model.

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HCC does not derive from the LPC/biliary compartment in the DEN+CCl4 mod...
Tamoxifen-treated Opn-CreERT2 mice were treated with DEN followed by 20 injections (20×) of CCl4 (n = 6). (A and B) Representative macroscopic (A) and histological images (B) showing typical HCC features such as high Ki67 expression levels and disruption of the collagen IV meshwork. Col IV, collagen IV. (C and D) The cholangiocyte/LPC compartment was YFP positive, but no HCCs were YFP positive (n = 6). (E) HCC and progenitor/hepatoblast markers determined by qPCR. (F–I) mTom-mGFP Cre reporter mice (n = 5) were treated with tamoxifen, followed by administration of DEN and 20 injections of CCl4 for HCC induction. Representative images and fluorescent images of livers (F) and H&E- and GFP-stained liver sections at low (G) and high (H) magnification, demonstrating mGFP-positive ducts in nontumor areas but not in tumor areas. Quantification of GFP-labeled K19-positive cholangiocytes and tumors (n = 5) (I). Sac, sacrifice. Scale bars: 1 cm (A and F); 100 μm (B and G); 50 μm (C and H). **P < 0.01, ***P < 0.001 by Mann-Whitney U test.