Format

Send to

Choose Destination
Am J Pathol. 2018 Mar;188(3):656-671. doi: 10.1016/j.ajpath.2017.11.013. Epub 2017 Dec 15.

Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice.

Author information

1
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
2
Department of Biochemistry, Purdue University, West Lafayette, Indiana.
3
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
4
Department of Statistics, St. Jude Children's Research Hospital, Memphis, Tennessee.
5
Department of Small Animal Imaging Core, St. Jude Children's Research Hospital, Memphis, Tennessee.
6
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
7
Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
8
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee. Electronic address: liqin.zhu@stjude.org.

Abstract

Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center