Maraviroc prevents hcc development by suppressing macrophages and the liver progenitor cell response in a murine chronic liver disease model

Adam M. Passman, Robyn P. Strauss, Sarah B. McSpadden, Megan Finch-Edmondson, Neil Andrewartha, Ken H. Woo, Luke A. Diepeveen, Weihao Zhao, Joaquín Fernández-Irigoyen, Enrique Santamaría, Laura Medina-Ruiz, Martyna Szpakowska, Andy Chevigné, Hyerin Park, Rodrigo Carlessi, Janina E.E. Tirnitz-Parker, José R. Blanco, Roslyn London, Bernard A. Callus, Caryn L. ElsegoodMurray V. Baker, Alfredo Martínez, George C.T. Yeoh, Laura Ochoa-Callejero*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investi-gated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supple-mented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Tran-script and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1-to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.

Original languageEnglish
Article number4935
JournalCancers
Volume13
Issue number19
DOIs
Publication statusPublished - Oct 2021

Keywords

  • CCL5 chemokine
  • Hepatocellular carcinoma
  • Liver progenitor cells
  • Macrophages
  • Mara-viroc

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