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

September 30, 2021 By:
  • Passman AM
  • Strauss RP
  • McSpadden SB
  • Finch-Edmondson M
  • Andrewartha N
  • Woo KH
  • Diepeveen LA
  • Zhao W
  • Fernandez-Irigoyen J
  • Santamaria E
  • Medina-Ruiz L
  • Szpakowska M
  • Chevigne A
  • Park H
  • Carlessi R
  • Tirnitz-Parker JEE
  • Blanco JR
  • London R
  • Callus BA
  • Elsegood CL
  • Baker MV
  • Martinez A
  • Yeoh GCT
  • Ochoa-Callejero L.

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.

2021 Sep. Cancers.13(19):4935.
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