A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations

Abstract

Activation-induced cytidine deaminase (AID) contributes to inflammation-associated carcinogenesis through its mutagenic activity. In our study, by taking advantage of the ability of AID to induce genetic aberrations, we investigated whether liver cancer originates from hepatic stem/progenitor cells that accumulate stepwise genetic alterations. For this purpose, hepatic progenitor cells enriched from the fetal liver of AID transgenic (Tg) mice were transplanted into recipient "toxin-receptor mediated conditional cell knockout" (TRECK) mice, which have enhanced liver regeneration activity under the condition of diphtheria toxin treatment. Whole exome sequencing was used to determine the landscape of the accumulated genetic alterations in the transplanted progenitor cells during tumorigenesis. Liver tumors developed in 7 of 11 (63.6%) recipient TRECK mice receiving enriched hepatic progenitor cells from AID Tg mice, while no tumorigenesis was observed in TRECK mice receiving hepatic progenitor cells of wild-type mice. Histologic examination revealed that the tumors showed characteristics of hepatocellular carcinoma and partial features of cholangiocarcinoma with expression of the AID transgene. Whole exome sequencing revealed that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice. Microarray analyses revealed that the majority of the mutations (>80%) were present in actively transcribed genes in the liver-lineage cells. These findings provided the evidence suggesting that accumulation of genetic alterations in fetal hepatic progenitor cells progressed to liver cancers, and the selection of mutagenesis depends on active transcription in the liver-lineage cells.

Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis

“…Consistently, AID expression is observed in hepatocytes of chronically inflamed HCV-infected liver, while AID expression is not observed in normal liver tissues [126,127]. In vivo studies revealed that constitutive AID expression promotes tumorigenesis by enhancing the susceptibility to mutagenesis in a variety of epithelial organs, including the liver [125,128,129]. These findings suggest that chronic inflammation caused by HCV infection triggers the aberrant upregulation of AID in hepatocytes, leading to the genomic instability required for tumorigenesis.…”

Stress‐induced cellular adaptive strategies: Ancient evolutionarily conserved programs as new anticancer therapeutic targets

“…This phenomenon was originally observed in bacteria , where genes transcribed during the stress response were more likely mutated than untranscribed genes. Transcription‐associated mutations have also been observed in yeast and mammalian cells . In this mechanism, mutations are targeted to expressed genes, the products of which are needed as part of adaptive programs.…”

“…Insights & Perspectives ..... genes. Transcription-associated mutations have also been observed in yeast [64] and mammalian cells [65]. In this mechanism, mutations are targeted to expressed genes, the products of which are needed as part of adaptive programs.…”

Novel Mouse Models of Hepatocarcinogenesis with Stepwise Accumulation of Genetic Alterations

“…Furthermore, whole exome sequencing of tumor cells allowed us to determine the landscape of the accumulated genetic alterations during tumorigenesis and clarified that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice. Pathway analysis using a KEGG database revealed that the acquired genetic aberrations affected several important signaling pathways, thereby disturbing normal homeostasis [31]. These results indicate that accumulation of genetic alterations in fetal hepatic progenitor cells could lead to HCC development.…”

“…We enriched hepatic progenitor cells from the E13.5 fetal liver of AID Tg mice and transplanted those cells, which have enhanced liver regeneration activity, into recipient mice. HCC developed in 7 out of 11 (63.6%) recipient mice receiving enriched hepatic progenitor cells from AID Tg mice, whereas no tumorigenesis was observed in recipient mice transplanted with hepatic progenitor cells from wild-type mice (control) [31]. Furthermore, whole exome sequencing of tumor cells allowed us to determine the landscape of the accumulated genetic alterations during tumorigenesis and clarified that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice.…”