Passman Adam M, Strauss Robyn P, McSpadden Sarah B, Finch-Edmondson Megan, Andrewartha Neil, Woo Ken H, Diepeveen Luke A, Zhao Weihao, Fernández-Irigoyen Joaquín, Santamaría Enrique, Medina-Ruiz Laura, Szpakowska Martyna, Chevigné Andy, Park Hyerin, Carlessi Rodrigo, Tirnitz-Parker Janina E E, Blanco José R, London Roslyn, Callus Bernard A, Elsegood Caryn L, Baker Murray V, Martínez Alfredo, Yeoh George C T, Ochoa-Callejero Laura
School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia.
Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia.
Cancers (Basel). 2021 Sep 30;13(19):4935. doi: 10.3390/cancers13194935.
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 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.
马拉维若（MVC）是一种CCR5拮抗剂，可减轻喂食肝癌致癌饮食的小鼠的肝纤维化、损伤和肿瘤负担，表明它具有作为癌症治疗药物的潜力。我们研究了MVC对肝祖细胞（LPCs）和巨噬细胞的影响，因为两者在肝癌发生过程中都起作用。给小鼠喂食肝癌致癌的胆碱缺乏、蛋氨酸补充饮食（CDE）±MVC，并用免疫组织化学、RNA和蛋白质表达来确定LPC和巨噬细胞的丰度、迁移及相关分子机制。MVC使CDE小鼠的LPC数量减少了54%，巨噬细胞数量减少幅度较小。LPC相关标志物的转录本和蛋白质丰度与这种减少相关。CDE饮食激活了AKT和STAT3的磷酸化，而MVC可抑制这种激活。在我们的模型中LPC不表达 ；相反，巨噬细胞表达高水平的这种受体，表明MVC的作用是通过靶向巨噬细胞介导的。MVC减少了肝脏中CD45+细胞和巨噬细胞的迁移，并阻断了CDE诱导的肝脏巨噬细胞从M1型向M2型肿瘤相关巨噬细胞（TAM）表型的转变。这些发现表明，MVC有潜力作为一种重新利用的治疗药物，用于治疗M2-TAM和LPC数量增加且肝癌发病率升高的慢性肝病。
