The Role of Fibrosis and Liver-Associated Fibroblasts in the Pathogenesis of Hepatocellular Carcinoma - PubMed (original) (raw)

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The Role of Fibrosis and Liver-Associated Fibroblasts in the Pathogenesis of Hepatocellular Carcinoma

Jacopo Baglieri et al. Int J Mol Sci. 2019.

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and lacks effective therapeutic approaches. Most HCC develops in the setting of chronic liver injury, hepatic inflammation, and fibrosis. Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) are key players in liver fibrogenesis and hepatocarcinogenesis, respectively. CAFs, which probably derive from HSCs, activate into extracellular matrix (ECM)-producing myofibroblasts and crosstalk with cancer cells to affect tumor growth and invasion. In this review, we describe the different components which form the HCC premalignant microenvironment (PME) and the tumor microenvironment (TME), focusing on the liver fibrosis process and the biology of CAFs. We will describe the CAF-dependent mechanisms which have been suggested to promote hepatocarcinogenesis, such as the alteration of ECM, CAF-dependent production of cytokines and angiogenic factors, CAF-dependent reduction of immuno-surveillance, and CAF-dependent promotion of epithelial-mesenchymal transition (EMT). New knowledge of the fibrosis process and the role of CAFs in HCC may pave the way for new therapeutic strategies for liver cancer.

Keywords: cancer-associated fibroblasts (CAFs); fibrosis; hepatic stellate cells (HSCs); hepatocellular carcinoma (HCC); tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript.

Figures

Figure 1

Figure 1

Mechanisms which promote HCC formation in PME. In PME, chronic liver injury causes hepatocyte death, which triggers inflammation, the activation of hepatic stellate cells into ECM-producing myofibroblasts, compensatory hepatocyte proliferation, the release of reactive oxygen species (ROS), and DNA damage. Continuous cycles of this destructive–regenerative process, which precedes tumor formation, are proposed to give rise to replication-related mutations in hepatocytes and eventually HCC. The links between the different mechanisms are indicated here.

Figure 2

Figure 2

TME in HCC. The figure outlines the different components of the TME and the CAF-dependent mechanisms of hepatocarcinogenesis. (See text for details).

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References

    1. Londoño M.C., Abraldes J.G., Altamirano J., Decaens T., Forns X. Clinical trial watch: Reports from the AASLD Liver Meeting®, Boston, November 2014. J. Hepatol. 2015;62:1196–1203. doi: 10.1016/j.jhep.2015.01.028. - DOI - PubMed
    1. Torre L.A., Bray F., Siegel R.L., Ferlay J., Lortet-Tieulent J., Jemal A. Global cancer statistics, 2012. CA Cancer J. Clin. 2015;65:87–108. doi: 10.3322/caac.21262. - DOI - PubMed
    1. El-Serag H.B. Hepatocellular carcinoma. N. Engl. J. Med. 2011;365:1118–1127. doi: 10.1056/NEJMra1001683. - DOI - PubMed
    1. Forner A., Reig M., Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–1314. doi: 10.1016/S0140-6736(18)30010-2. - DOI - PubMed
    1. Friedman S.L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J. Biol. Chem. 2000;275:2247–2250. doi: 10.1074/jbc.275.4.2247. - DOI - PubMed

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