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

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. (2021) Maraviroc prevents HCC development by suppressing macrophages and the liver progenitor cell response in a murine chronic liver disease model. Cancers, 13 (19). Article 4935.

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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: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
Publisher: MDPI
Copyright: © 2021 by the authors
URI: http://researchrepository.murdoch.edu.au/id/eprint/62432
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