PMID- 34638423 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20211016 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 13 IP - 19 DP - 2021 Sep 30 TI - Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model. LID - 10.3390/cancers13194935 [doi] LID - 4935 AB - 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. FAU - Passman, Adam M AU - Passman AM AUID- ORCID: 0000-0003-3212-6938 AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. FAU - Strauss, Robyn P AU - Strauss RP AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. FAU - McSpadden, Sarah B AU - McSpadden SB AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. FAU - Finch-Edmondson, Megan AU - Finch-Edmondson M AUID- ORCID: 0000-0002-9628-5842 AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. FAU - Andrewartha, Neil AU - Andrewartha N AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. FAU - Woo, Ken H AU - Woo KH AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. FAU - Diepeveen, Luke A AU - Diepeveen LA AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. FAU - Zhao, Weihao AU - Zhao W AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. FAU - Fernandez-Irigoyen, Joaquin AU - Fernandez-Irigoyen J AD - Proteored-ISCIII, Proteomics Platform, Navarrabiomed, Navarra Health Department, Navarra Institute for Health Research (IdiSNA), Public University of Navarra, 31008 Pamplona, Spain. FAU - Santamaria, Enrique AU - Santamaria E AUID- ORCID: 0000-0001-8046-8102 AD - Proteored-ISCIII, Proteomics Platform, Navarrabiomed, Navarra Health Department, Navarra Institute for Health Research (IdiSNA), Public University of Navarra, 31008 Pamplona, Spain. FAU - Medina-Ruiz, Laura AU - Medina-Ruiz L AD - Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Center, University of Glasgow, Glasgow G12 8TA, UK. FAU - Szpakowska, Martyna AU - Szpakowska M AUID- ORCID: 0000-0002-5659-8377 AD - Immuno-Pharmacology and Interactomics Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg. FAU - Chevigne, Andy AU - Chevigne A AUID- ORCID: 0000-0003-4768-6743 AD - Immuno-Pharmacology and Interactomics Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg. FAU - Park, Hyerin AU - Park H AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. AD - UWA Medical School, University of Western Australia, Crawley, WA 6009, Australia. FAU - Carlessi, Rodrigo AU - Carlessi R AUID- ORCID: 0000-0003-0038-7391 AD - Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia. FAU - Tirnitz-Parker, Janina E E AU - Tirnitz-Parker JEE AD - Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia. FAU - Blanco, Jose R AU - Blanco JR AUID- ORCID: 0000-0002-4268-0150 AD - Infectious Diseases Area, Hospital San Pedro-Center for Biomedical Research of La Rioja, 26006 Logrono, Spain. FAU - London, Roslyn AU - London R AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. FAU - Callus, Bernard A AU - Callus BA AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Comparative Genomics, Murdoch University, Murdoch, WA 6150, Australia. FAU - Elsegood, Caryn L AU - Elsegood CL AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. AD - UWA Medical School, University of Western Australia, Crawley, WA 6009, Australia. AD - Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia. FAU - Baker, Murray V AU - Baker MV AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. FAU - Martinez, Alfredo AU - Martinez A AUID- ORCID: 0000-0003-4882-4044 AD - Oncology Area, Center for Biomedical Research of La Rioja, 26006 Logrono, Spain. FAU - Yeoh, George C T AU - Yeoh GCT AD - School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. AD - Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. FAU - Ochoa-Callejero, Laura AU - Ochoa-Callejero L AUID- ORCID: 0000-0001-5366-6613 AD - Oncology Area, Center for Biomedical Research of La Rioja, 26006 Logrono, Spain. LA - eng GR - 15/10358798/Luxembourg National Research Fund/ GR - PT17/0019/009/The Proteomics Platform of Navarrabiomed (PRB3-ISCIII)/ GR - 7.4593.19/F.R.S.-FNRS-Televie/ GR - 7.4529.19/F.R.S.-FNRS-Televie/ GR - 7.8504.20/F.R.S.-FNRS-Televie/ PT - Journal Article DEP - 20210930 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC8508380 OTO - NOTNLM OT - CCL5 chemokine OT - Maraviroc OT - hepatocellular carcinoma OT - liver progenitor cells OT - macrophages COIS- J.R.B. has carried out consulting work for AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare and has received compensation for lectures from AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare, as well as grants and payments for the development of educational presentations for Gilead Sciences, Bristol Myers Squibb and ViiV Healthcare. EDAT- 2021/10/14 06:00 MHDA- 2021/10/14 06:01 PMCR- 2021/09/30 CRDT- 2021/10/13 01:01 PHST- 2021/07/15 00:00 [received] PHST- 2021/09/20 00:00 [revised] PHST- 2021/09/26 00:00 [accepted] PHST- 2021/10/13 01:01 [entrez] PHST- 2021/10/14 06:00 [pubmed] PHST- 2021/10/14 06:01 [medline] PHST- 2021/09/30 00:00 [pmc-release] AID - cancers13194935 [pii] AID - cancers-13-04935 [pii] AID - 10.3390/cancers13194935 [doi] PST - epublish SO - Cancers (Basel). 2021 Sep 30;13(19):4935. doi: 10.3390/cancers13194935.