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Animal models of HCC – When injury meets mutation

Published:November 16, 2017DOI:https://doi.org/10.1016/j.jhep.2017.07.023
      Most hepatocellular carcinomas (HCCs) develop in patients with liver cirrhosis as a consequence of long-term liver injury, and can be ascribed to one or several etiological factors including chronic viral hepatitis, alcoholic or non-alcoholic fatty liver disease or aflatoxin ingestion.
      • El-Serag H.B.
      Hepatocellular carcinoma.
      Moreover, a wide range of mutations and signaling pathways that drive hepatocarcinogenesis have been identified, even though they vary widely between patients.
      • Schulze K.
      • Imbeaud S.
      • Letouze E.
      • Alexandrov L.B.
      • Calderaro J.
      • Rebouissou S.
      • et al.
      Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.
      Ideally, incorporation of etiological factors and mutations into animal models could result in a translational model resembling human HCC. However, despite the large number of animal models for HCC,
      • Caviglia J.M.
      • Schwabe R.F.
      Mouse models of liver cancer.
      there is a lack of widely accepted models that incorporate causative agents and key pathophysiological aspects of human HCC: Hepatitis viruses do not infect mice or rats unless they have been humanized; there is no good model of chronic alcoholic liver injury; murine non-alcoholic steatohepatitis (NASH) models often result in weak fibrosis and require 15 months for tumors to develop in a significant proportion of mice.
      • Caviglia J.M.
      • Schwabe R.F.
      Mouse models of liver cancer.
      In addition, most genetic HCC models that reproduce common genetic alterations of human HCC, e.g. mutations in CTNNB1 or TP53 or activation of Ras or Akt pathways, typically lack chronic injury, inflammation, and fibrosis, meaning that HCCs develop in almost normal livers. Moreover, little is known about the genetic landscape of models in which HCC develops as a consequence of chronic injury, inflammation and fibrosis, e.g. Mdr2ko mice, mice subjected to long-term dietary NASH models, mice with hepatocyte-specific deletion of Nemo, Tak1 or Mcl-1, or mice treated with diethylnitrosamine in combination with carbon tetrachloride (CCl4).

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