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

Passman, A. M. et al. (2021) Maraviroc prevents HCC development by suppressing macrophages and the liver progenitor cell response in a murine chronic liver disease model. Cancers, 13(19), 4935. (doi: 10.3390/cancers13194935) (PMID:34638423) (PMCID:PMC8508380)

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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 investigated 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-supplemented 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. Transcript 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.

Item Type:Articles
Keywords:CCL5 chemokine, hepatocellular carcinoma, liver progenitor cells, macrophages, Maraviroc.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Medina-Ruiz, Dr Laura
Creator Roles:
Medina-Ruiz, L.Investigation
Authors: Passman, A. M., Strauss, R. P., McSpadden, S. B., Finch-Edmondson, M., Andrewartha, N., Woo, K. H., Diepeveen, L. A., Zhao, W., Fernández-Irigoyen, J., Santamaría, E., Medina-Ruiz, L., Szpakowska, M., Chevigné, A., Park, H., Carlessi, R., Tirnitz-Parker, J. E. E., Blanco, J. R., London, R., Callus, B. A., Elsegood, C. L., Baker, M. V., Martínez, A., Yeoh, G. C.T., and Ochoa-Callejero, L.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Cancers
Publisher:MDPI
ISSN:2072-6694
ISSN (Online):2072-6694
Published Online:30 September 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Cancers 13(19): 4935
Publisher Policy:Reproduced under a Creative Commons License

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