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.
Highlights
Hepatocellular carcinoma (HCC), a type of epithelial cancer, is the most common primary liver cancer (80–90%) in the United States [1]
Total protein was extracted from malignant tissues as well as the paired adjacent benign tissues from 24 hepatocellular carcinoma (HCC) patients, while the protein levels of β-catenin and epithelial cell adhesion molecule (EpCAM) were evaluated by Western blot from 8 HCC patients
Western blot analysis confirmed that EpCAM and β-catenin expression were positively correlated in the HCC patient samples
Summary
Hepatocellular carcinoma (HCC), a type of epithelial cancer, is the most common primary liver cancer (80–90%) in the United States [1]. A subset of cancer cells within the tumor microenvironment, defined as cancer stem cells (CSCs), contributes to aggressive tumor initiation, therapeutic treatment resistance, and tumor relapse in HCC patients [5]. The CSC concept has been elucidated in regard to tumor heterogeneity within primary HCC, and it helps to understand therapeutic resistance and early relapse [5,6,7]. EpCAM, one of the most characterized and well-accepted CSC markers, is associated with poor prognosis in HCC patients [10,11,12,13,14]. There is no previous study to investigate EpCAM-expressing CSCs for their tumorigenic ability in a compromised liver microenvironment such as non-alcoholic fatty liver disease (NAFLD)
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