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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

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 1

HCC does not derive from the LPC/biliary compartment.

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HCC does not derive from the LPC/biliary compartment.
Tamoxifen-treated ...
Tamoxifen-treated Opn-CreERT2 mice expressing the YFP Cre reporter were subjected to 25 injections of DEN (n = 33). (A and B) Mice developed macroscopically (A) and microscopically (B) visible HCCs. Tam, tamoxifen. (C and D) While the K19-positive biliary/LPC compartment was tagged efficiently by YFP, no HCCs were YFP positive. HCCs were delineated by an α-SMA–positive border and infiltrated by myofibroblasts; HCCs displayed a disrupted reticulin meshwork, high Ki67 expression levels, focally expressed OPN and AFP, and were surrounded by a patchy K19-positive and YFP-positive DR. Scale bars: 1 cm (A and B); 100 μm (D). Chol, cholangiocyte; NT, nontumor; T, tumor.
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