Poster Presentation 26th Lorne Cancer Conference 2014

Inhibition of the liver progenitor cell response and tumour burden by the CCR5 antagonist, Maraviroc (#229)

Adam Passman 1 2 , Sarah McSpadden 1 2 , Robyn Strauss 1 2 , Megan Finch 1 2 , Roslyn London 1 2 , Bernard Callus 1 2 , José R Blanco 3 , Laura Ochoa-Callejero 4 , George Yeoh 1 2
  1. University of Western Australia, Crawley, WA, Australia
  2. Western Australian Institute for Medical Research, Perth, WA, Australia
  3. Infectious Diseases, Center for Biomedical Research of La Rioja, Logroño, Spain
  4. Oncology, Center for Biomedical Research of La Rioja, Logroño, Spain

Hepatocellular carcinoma (HCC) is the 6th most common malignancy worldwide and third in cancer-related deaths. The molecular mechanisms causing HCC remain poorly understood and treatments are largely ineffective. Mounting evidence suggests an association between liver progenitor cells (LPC) and HCC development. The choline-deficient, ethionine-supplemented (CDE) dietary model of hepatocarcinogenesis is used to study this phenomenon. This diet closely mimics human liver disease progression, inducing LPCs and fatty liver then fibrosis, cirrhosis and finally HCC. A recent study used this model in conjunction with Maraviroc (Pfizer), a CCR5 antagonist.1  Mice fed the CDE diet without Maraviroc (CDE) experienced liver injury, characterised by fibrosis, apoptosis, proliferation and HCC within 4 months. In contrast, mice fed the CDE diet and given Maraviroc (CDE+MVC) had significantly reduced liver injury and tumour burden. Using these same samples, we investigated the possible link between LPC and HCC development by documenting the effect of Maraviroc, in modulating the LPC response. Immunohistological staining with PanCK, indicating LPC abundance, was quantified using Aperio ImageScope positive pixel analysis. PanCK pixel positivity was increased in livers of CDE and CDE+MVC mice, compared to those fed control and control+MVC chow. Interestingly, PanCK positivity was reduced by 54% in mice given CDE+MVC compared to those fed the CDE diet alone. Transcript levels of several LPC-associated genes (Sox9, Ncam, Ck19, Cd133, M2pk and Cd24a) corresponded with PanCK staining results. Furthermore, protein expression levels of several LPC markers were also attenuated in the CDE+MVC group. Together these results suggest that Maraviroc may reduce tumour formation by modulating LPC levels in CDE livers.

  1. Ochoa-Callejero et al, PLoS One 2013