Research Papers:

Carcinogenetic initiation contributed by EpCAM+ cancer cells in orthotopic HCC models of immunocompetent and athymic mice

Harshul Pandit, Yan Li, Qianqian Zheng, Wei Guo, Youxi Yu, Suping Li and Robert C.G. Martin _

PDF  |  Full Text  |  Supplementary Files  |  How to cite

Oncotarget. 2020; 11:2047-2060. https://doi.org/10.18632/oncotarget.27454

Metrics: PDF 2076 views  |   Full Text 2749 views  |   ?  


Harshul Pandit1,5, Yan Li1,5, Qianqian Zheng2, Wei Guo3, Youxi Yu4, Suping Li1 and Robert C.G. Martin1,5

1 Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA

2 Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang 110122, China

3 Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China

4 Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China

5 Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA

Correspondence to:

Robert C.G. Martin,email: [email protected]

Keywords: hepatocellular carcinoma; Wnt/β-catenin signaling; cancer stem cells; epithelial cell adhesion molecule (EpCAM); tumor-initiating cells

Received: October 30, 2019     Accepted: December 26, 2019     Published: June 02, 2020


Purpose: Overexpression of epithelial cell adhesion molecule (EpCAM) correlates with poor prognosis, therapeutic failure and early tumor recurrence in hepatocellular carcinoma (HCC) patients. The tumor microenvironment dictates the fate of tumor-initiating cancer stem cells (CSCs); however, very limited studies were attempted to evaluate CSC tumorigenesis in the liver microenvironment. Here, we have systemically investigated the role of EpCAM+ cancer cells in tumor initiation in orthotopic HCC models.

Results: Control mice and the mice with bland steatosis failed to develop tumors. In the mice with steatohepatitis, EpCAM+ CSCs have shown significantly increased ability in terms of tumor initiation and growth, compared to that with EpCAM- non-CSCs inoculation (p < 0.005). For Hep3B inoculation, EpCAM-High group has shown significantly higher tumor growth compared with EpCAM-Low (p < 0.005). For HepG2 inoculation, both EpCAM-High and EpCAM-Low groups confirmed similar tumor incidence and growth.

Methods: Diet-induced compromised microenvironments were established to mimic clinical fatty liver and non-alcoholic steatohepatitis (NASH) patients and the tumorigenic capabilities of Hepa1-6 cells were evaluated. CSCs were enriched by spheroid culture and labeled with copGFP for EpCAM+ CSCs and with mCherry for non-CSCs. FACS-sorted cells were inoculated into left liver lobes, and tumor growth was monitored by high-frequency ultrasound. The subpopulations of Hep3B and HepG2 cells in terms of EpCAM-Low and EpCAM-High were evaluated in the orthotopic model of athymic mice.

Conclusions: NASH microenvironment promotes the EpCAM+ CSCs initiated tumorigenesis in immunocompetent mouse model. Differential EpCAM expression demonstrates distinct tumor biology in athymic mouse models.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 27454