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Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model

1
School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia
2
Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia
3
Proteored-ISCIII, Proteomics Platform, Navarrabiomed, Navarra Health Department, Navarra Institute for Health Research (IdiSNA), Public University of Navarra, 31008 Pamplona, Spain
4
Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Center, University of Glasgow, Glasgow G12 8TA, UK
5
Immuno-Pharmacology and Interactomics Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg
6
UWA Medical School, University of Western Australia, Crawley, WA 6009, Australia
7
Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
8
Infectious Diseases Area, Hospital San Pedro—Center for Biomedical Research of La Rioja, 26006 Logroño, Spain
9
Centre for Comparative Genomics, Murdoch University, Murdoch, WA 6150, Australia
10
Oncology Area, Center for Biomedical Research of La Rioja, 26006 Logroño, Spain
*
Author to whom correspondence should be addressed.
A.M.P. is now at Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
M.L.F.-E. is now at the Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2100, Australia.
§
Sharing senior authorship.
Academic Editor: David Wong
Cancers 2021, 13(19), 4935; https://doi.org/10.3390/cancers13194935
Received: 15 July 2021 / Revised: 20 September 2021 / Accepted: 26 September 2021 / Published: 30 September 2021
(This article belongs to the Topic Animal Model in Biomedical Research)
Liver stem cells and activated macrophages have been implicated as contributors to liver cancer; hence, reducing their abundance is a potential avenue for therapy. In this article, we demonstrate that Maraviroc, a drug approved for human use, reduces the liver stem cell response and macrophage activation in a mouse model of liver cancer. These findings underline the preventive potential of this drug in liver cancer, a deadly disease for which there are few effective treatments.
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. View Full-Text
Keywords: CCL5 chemokine; hepatocellular carcinoma; liver progenitor cells; macrophages; Maraviroc CCL5 chemokine; hepatocellular carcinoma; liver progenitor cells; macrophages; Maraviroc
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MDPI and ACS Style

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.; Ochoa-Callejero, L. Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model. Cancers 2021, 13, 4935. https://doi.org/10.3390/cancers13194935

AMA Style

Passman AM, Strauss RP, McSpadden SB, Finch-Edmondson M, Andrewartha N, Woo KH, Diepeveen LA, Zhao W, Fernández-Irigoyen J, Santamaría E, Medina-Ruiz L, Szpakowska M, Chevigné A, Park H, Carlessi R, Tirnitz-Parker JEE, Blanco JR, London R, Callus BA, Elsegood CL, Baker MV, Martínez A, Yeoh GCT, Ochoa-Callejero L. Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model. Cancers. 2021; 13(19):4935. https://doi.org/10.3390/cancers13194935

Chicago/Turabian Style

Passman, Adam M., 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. Elsegood, Murray V. Baker, Alfredo Martínez, George C. T. Yeoh, and Laura Ochoa-Callejero. 2021. "Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model" Cancers 13, no. 19: 4935. https://doi.org/10.3390/cancers13194935

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