Novel short-termed mouse model of intrahepatic cholangiocarcinoma by orthotopic transplantation of Hep-55.1C in mice with human homology

Background Intrahepatic cholangiocarcinoma (ICC) is a highly malignant and progressive cancer that ranks the second most common liver cancer. To further understand molecular mechanisms of rise and progression of cholangiocarcinoma animal models are needed. Next to carcinogen-induced ICC-models or genetically engineered models, there are only few allograft or xenograft transplant models that claim challenging operative techniques or longer time periods for tumor development.

Method Hep55.1C cells were injected in the liver of 6-8 weeks old C57/B6 male mice. Tumor growth was followed by weekly ultrasound. After two or four weeks respectively mice were sacrificed. ICC and the tumor microenvironment were characterized via qRT-PCR, histological characterization/ multiplex imaging, flow cytometry and RNAseq. Murine data were comprehensively correlated with human data.

Results Tumor size was 0.6cm² or 1cm² on average after two or four weeks after transplantation with a prevalence 100%. Tumor tissue in comparison to surrounding tissue showed high expression of cholangiocyte markers but not hepatocyte markers or markers for hepatocellular carcinoma. Immunohistological staining revealed a strong and ubiquitous signal for Pan-Cytokeratin within the tumor but not the surrounding tissue in contrast to HNF4α that was upregulated in the surrounding tissue. The analysis of the tumor microenvironment revealed a strong human homology regarding proliferation, gene expression pattern, tumor-associated immune response and stromal composition.

Conclusion We here present a new intrahepatic cholangiocarinoma mouse model with human homology. Tumor induction shows a 100% success rate with macroscopic tumor growth within few weeks. Our model is therefore most suitable to evaluate interventional therapies.

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Artikel online veröffentlicht:
26. Januar 2022