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  • Review Article
  • Published:

Functional and genetic deconstruction of the cellular origin in liver cancer

Key Points

  • Primary liver cancers (PLCs), including the most common subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), are characterized by molecular and phenotypic heterogeneity, which impedes therapeutic progress.

  • Chronic inflammation of the hepatic microenvironment is a hallmark feature of the majority of PLCs.

  • Although no clear oncogene addiction is recognized in PLCs, most common genetic alterations are detected in key cancer genes, such as TP53, WNTCTNNB1 (which encodes β-catenin) and cell cycle-related genes. Other frequent changes are found in telomere maintenance (telomerase reverse transcriptase (TERT)), chromatin modifiers and inflammatory pathways.

  • Depending on the target cell of malignant transformation — that is, the cell of origin — a broad range of different phenotypes, from classic HCC and iCCA to mixed HCC–iCCA lesions, is observed.

  • The putative cellular origin in PLCs is diverse and not clearly defined. The differentiation state of the cell (or cells) of origin might determine the tumour biology.

  • Tumours that have progenitor cell traits display activation of adverse signalling pathways and a poor overall outcome.

  • Crosstalk between cancer cells and the altered hepatic tumour microenvironment can promote disease progression and might be a promising new therapeutic target.

  • The identification of novel cellular and molecular targets requires integrative approaches. Precision medicine using next-generation technologies (whole-exome and RNA sequencing, and methylation profiling) and integration of individual tumour characteristics will be needed to improve the dismal outcome for patients with PLC.

Abstract

During the past decade, research on primary liver cancers has particularly highlighted the uncommon plasticity of differentiated parenchymal liver cells (that is, hepatocytes and cholangiocytes (also known as biliary epithelial cells)), the role of liver progenitor cells in malignant transformation, the importance of the tumour microenvironment and the molecular complexity of liver tumours. Whereas other reviews have focused on the landscape of genetic alterations that promote development and progression of primary liver cancers and the role of the tumour microenvironment, the crucial importance of the cellular origin of liver cancer has been much less explored. Therefore, in this Review, we emphasize the importance and complexity of the cellular origin in tumour initiation and progression, and attempt to integrate this aspect with recent discoveries in tumour genomics and the contribution of the disrupted hepatic microenvironment to liver carcinogenesis.

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Figure 1: Sequential evolution of PLC.
Figure 2: The landscape of genetic alterations in PLC.
Figure 3: Anatomical architecture of the liver and localization of PLC.
Figure 4: Putative cell of origin in PLC.

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Acknowledgements

This project was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA (to S.S.T.). J.U.M. is supported by grants from the German Research Foundation (MA 4443/2-1), German Cancer Aid (DKH 110989) and the Volkswagen Foundation (Lichtenberg program). J.B.A. is supported by grants from the Danish Cancer Society (Knæk cancer program), the Novo Nordisk Foundation (Hallas-Møller fellowship), the Danish Medical Research Council (Sapere Aude program) and the A.P. Møller Foundation.

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Glossary

Liver cirrhosis

A slow and progressive replacement of healthy liver tissue by fibrotic scar tissue, with subsequent loss of organ function. Cirrhosis occurs as the common end point of the majority of chronic liver diseases.

Precision medicine

A form of treatment that focuses on the individual factors of a disease and uses next-generation technologies to improve therapy.

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(Multicentric hepatocellular carcinomas). More than one independent tumour with different clonal origins detected in the liver.

Genome substitution patterns

Patterns of nucleotide substitution across the whole tumour genome. Characteristic patterns can be detected in different tumours and/or aetiological backgrounds.

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Conversion of somatic cells to a more stem-like state or to a different developmental lineage.

Hydrodynamic gene delivery

A highly efficient method for delivery of membrane-impermeable genetic information by physical force. A solution is rapidly injected at high volume to enable the delivery of genetic information to the target cell.

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Marquardt, J., Andersen, J. & Thorgeirsson, S. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat Rev Cancer 15, 653–667 (2015). https://doi.org/10.1038/nrc4017

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