TY - JOUR
T1 - Maraviroc prevents hcc development by suppressing macrophages and the liver progenitor cell response in a murine chronic liver disease model
AU - Passman, Adam M.
AU - Strauss, Robyn P.
AU - McSpadden, Sarah B.
AU - Finch-Edmondson, Megan
AU - Andrewartha, Neil
AU - Woo, Ken H.
AU - Diepeveen, Luke A.
AU - Zhao, Weihao
AU - Fernández-Irigoyen, Joaquín
AU - Santamaría, Enrique
AU - Medina-Ruiz, Laura
AU - Szpakowska, Martyna
AU - Chevigné, Andy
AU - Park, Hyerin
AU - Carlessi, Rodrigo
AU - Tirnitz-Parker, Janina E.E.
AU - Blanco, José R.
AU - London, Roslyn
AU - Callus, Bernard A.
AU - Elsegood, Caryn L.
AU - Baker, Murray V.
AU - Martínez, Alfredo
AU - Yeoh, George C.T.
AU - Ochoa-Callejero, Laura
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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 investi-gated 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.
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 investi-gated 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.
KW - CCL5 chemokine
KW - Hepatocellular carcinoma
KW - Liver progenitor cells
KW - Macrophages
KW - Mara-viroc
UR - http://www.scopus.com/inward/record.url?scp=85116065788&partnerID=8YFLogxK
U2 - 10.3390/cancers13194935
DO - 10.3390/cancers13194935
M3 - Article
C2 - 34638423
AN - SCOPUS:85116065788
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 19
M1 - 4935
ER -