Oncotarget

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 _

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

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Abstract

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

ABSTRACT

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.


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