Establishment of liver tumor cell lines from atherogenic and high fat diet fed hepatitis C virus transgenic mice

Takayoshi Shirasaki,Kazuhisa Murai,Tetsuro Shimakami,Kazunori Kawaguchi,Shuichi Kaneko,Yoshio Sakai,Atsumu Yamada,Taro Yamashita,Yuika Innami,Masao Honda,Hikari Okada

doi:10.1038/s41598-021-92128-9

Abstract

A syngeneic mouse model bearing a transplanted tumor is indispensable for the evaluation of the efficacy of immune checkpoint inhibitors (ICIs). However, few syngeneic mouse models of liver cancer are available. We established liver tumor cell lines (MHCF1 and MHCF5) from hepatitis C virus transgenic mice fed an atherogenic high-fat diet. MHCF1 and MHCF5 were successfully transplanted into the subcutaneous space of syngeneic C57BL/6 mice, in addition, they efficiently developed orthotopic tumors in the liver of syngeneic C57BL/6 mice. MHCF5 grew rapidly and showed a more malignant phenotype compared with MHCF1. Histologically, MHCF1-derived tumors were a combined type of hepatocellular carcinoma and MHCF5-derived tumors showed a sarcomatous morphology. Interestingly, MHCF1 and MHCF5 showed different sensitivity against an anti-PD1 antibody and MHCF5-derived tumors were resistant to this antibody. CD8 T cells infiltrated the MHCF1-derived tumors, but no CD8 T cells were found within the MHCF5-derived tumors. Gene expression profiling and whole-exon sequencing revealed that MHCF5 displayed the features of an activated cancer stem cell-like signature of sonic hedgehog and Wnt signaling. Therefore, these cell lines could be useful for the identification of new biomarkers and molecular mechanisms of ICI resistance and the development of new drugs against liver cancer.

Highlights

A syngeneic mouse model bearing a transplanted tumor is indispensable for the evaluation of the efficacy of immune checkpoint inhibitors (ICIs)
Abbreviations Ath + HFD Atherogenic and high-fat diet cholangiocellular carcinoma (CCC) Cholangiocellular carcinoma hepatocellular carcinoma (HCC) Hepatocellular carcinoma HCV Hepatitis C virus ICIs Immune checkpoint inhibitors MHCF1 Mouse liver tumor cells derived from full-length hepatitis C virus transgenic no. 1 MHCF5 Mouse liver tumor cells derived from full-length hepatitis C virus transgenic no. 5 platelet-derived growth factor c (Pdgfc) Platelet-derived growth factor c Tg Transgenic tyrosine kinase inhibitors (TKIs) Tyrosine kinase inhibitors
Treatment using ICIs for liver cancer has yielded some encouraging results, but the percentage of patients responding to single-agent therapies remains low

Summary

Introduction

A syngeneic mouse model bearing a transplanted tumor is indispensable for the evaluation of the efficacy of immune checkpoint inhibitors (ICIs). Gene expression profiling and whole-exon sequencing revealed that MHCF5 displayed the features of an activated cancer stem cell-like signature of sonic hedgehog and Wnt signaling. These cell lines could be useful for the identification of new biomarkers and molecular mechanisms of ICI resistance and the development of new drugs against liver cancer. Abbreviations Ath + HFD Atherogenic and high-fat diet CCC Cholangiocellular carcinoma HCC Hepatocellular carcinoma HCV Hepatitis C virus ICIs Immune checkpoint inhibitors MHCF1 Mouse liver tumor cells derived from full-length hepatitis C virus transgenic no. It is important to develop an effective combination therapy with ICIs and chemotherapy including biologic drugs or T KIs3,5

Methods

Results

Conclusion