Abstract

The urgent unmet need for hepatocellular carcinoma (HCC) therapies is addressed here by characterising a novel mouse model of HCC in the context of ongoing liver damage and overnutrition. Male C57Bl/6J mice were treated with diethylnitrosamine (DEN) and thioacetamide (TAA), and some were provided with an atherogenic high fat diet (HFD). Inflammation, steatosis, fibrosis, 87 genes, liver lesions and intratumoural leukocyte subsets were quantified up to 24 weeks of age. Adding HFD to DEN/TAA increased fibrosis, steatosis and inflammation, and the incidence of both HCC and non-HCC dysplastic lesions. All lesions contained α-SMA positive fibroblasts. Macrophage marker F4/80 was not significantly different between treatment groups, but the macrophage-associated genes Arg-1 and Cd47 were differentially expressed. Fibrosis, cancer and cell death associated genes were upregulated in DEN/TAA/HFD livers. Fewer Kupffer cells and plasmacytoid dendritic cells were in tumours compared to control liver. In conclusion, combining a hepatotoxin with an atherogenic diet produced more intrahepatic tumours, dysplastic lesions and fibrosis compared to hepatotoxin alone. This new HCC model provides a relatively rapid means of examining primary HCC and potential therapies in the context of multiple hepatotoxins including those derived from overnutrition.

Details

Title
Multiple liver insults synergize to accelerate experimental hepatocellular carcinoma
Author
Henderson, James M 1 ; Polak, Natasa 1 ; Chen, Jinbiao 1   VIAFID ORCID Logo  ; Roediger, Ben 1 ; Weninger, Wolfgang 2 ; Kench, James G 3 ; McCaughan, Geoffrey W 2 ; Zhang, Hui Emma 1 ; Gorrell, Mark D 4   VIAFID ORCID Logo 

1  Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia; The University of Sydney Faculty of Medicine and Health, New South Wales, Australia 
2  Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia; The University of Sydney Faculty of Medicine and Health, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia 
3  The University of Sydney Faculty of Medicine and Health, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia 
4  Centenary Institute, The University of Sydney, Newtown, New South Wales, Australia; The University of Sydney Faculty of Medicine and Health, New South Wales, Australia; Charles Perkins Centre, The University of Sydney, New South Wales, 2006, Australia 
Pages
1-12
Publication year
2018
Publication date
Jul 2018
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-018-28486-8
ProQuest document ID
2065388034
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.