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

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dc.contributor.authorPassman, Adam M.
dc.contributor.authorStrauss, Robyn P.
dc.contributor.authorMcSpadden, Sarah B.
dc.contributor.authorFinch-Edmondson, Megan
dc.contributor.authorAndrewartha, Neil
dc.contributor.authorWoo, Ken H.
dc.contributor.authorDiepeveen, Luke A.
dc.contributor.authorZhao, Weihao
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorMedina-Ruiz, Laura
dc.contributor.authorSzpakowska, Martyna
dc.contributor.authorChevigné, Andy
dc.contributor.authorPark, Hyerin
dc.contributor.authorCarlessi, Rodrigo
dc.contributor.authorTirnitz-Parker, Janina
dc.contributor.authorBlanco, José R.
dc.contributor.authorLondon, Roslyn
dc.contributor.authorCallus, Bernard A.
dc.contributor.authorElsegood, Caryn L.
dc.contributor.authorBaker, Murray V.
dc.contributor.authorMartínez, Alfredo
dc.contributor.authorYeoh, George C.T.
dc.contributor.authorOchoa-Callejero, Laura
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2022-04-12T08:44:44Z
dc.date.available2022-04-12T08:44:44Z
dc.date.issued2021
dc.description.abstractMaraviroc (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-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.en
dc.description.sponsorshipThis study was supported by UICC Yamagiwa-Yoshida Memorial International Cancer Study Fellowships (YY), Instituto de Estudios Riojanos (IER), Fundación Rioja Salud (FRS) and Luxembourg National Research Fund (INTER/FWO 'Nanokine' grant 15/10358798) and F.R.S.-FNRS-Télévie (grants 7.4593.19, 7.4529.19 and 7.8504.20). It also received support from the National Health and Medical Research Council of Australia, the Cancer Council of Western Australia, the Western Australian Cancer Single Cell Consortium and The Ride to Conquer Cancer. The Proteomics Platform of Navarrabiomed is a member of Proteored (PRB3-ISCIII) and is supported by grant PT17/0019/009 of the PE I+D+I 2013-2016 funded by ISCIII and FEDER.en
dc.format.extent21 p.
dc.format.mimetypeapplication/pdfen
dc.identifier.doi10.3390/cancers13194935
dc.identifier.issn2072-6694
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/42707
dc.language.isoengen
dc.publisherMDPIen
dc.relation.ispartofCancers 2021, 13, 4935en
dc.relation.publisherversionhttps://doi.org/10.3390/cancers13194935
dc.rights© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCCL5 chemokineen
dc.subjectHepatocellular carcinomaen
dc.subjectLiver progenitor cellsen
dc.subjectMacrophagesen
dc.subjectMara-virocen
dc.titleMaraviroc prevents hcc development by suppressing macrophages and the liver progenitor cell response in a murine chronic liver disease modelen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication.latestForDiscovery86d1b76e-4790-40b1-a3ec-72331c5c6199

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