The effect of hepatic progenitor cells on experimental hepatocellular carcinoma in the regenerating liver

Abstract

Objective. Liver regeneration following hepatectomy can stimulate the growth of hepatocellular carcinoma (HCC), and major hepatectomy can be associated with activation of hepatic progenitor cells (HPCs). The aim of this study was to evaluate how HPCs influence the malignant potential of tumor cells in vitro and HCC tumor growth after surgery in a rodent model. Material and methods. Hepatoma cells (JM1) were cultured with conditioned medium (CM) from syngeneic HPCs (WB-F344). Growth rate, resistance to Adriamycin, and expression patterns for invasiveness and stemness were compared with naïve JM1. Microscopic HCC tumors from naïve JM1 or JM1 cultured with CM were inoculated in Fischer 344 rats undergoing 70% hepatectomy with or without simultaneous infusion of WB-F344. Tumor growth and invasiveness-related factors were compared. Buffalo rats were induced with Morris hepatoma cells. Liver tissue from both in vivo models was examined with regard to activation of cells with progenitor-like phenotype. Results. Co-culture with CM resulted in an increased resistance to Adriamycin and enhanced expressions of α-FP, MMP9, ABCG2, CD133, and SOX2, as well as the activation of ERK, AKT, WNT, and TGF-β1 pathways. Tumor size and metastases were significantly higher in groups with co-cultured cells or HPCs infusion. After 70% hepatectomy and tumor implantation, cells positive for α-FP, CK19, and CD133 were found, thus suggesting a progenitor-like phenotype in the setting of epithelial-mesenchymal transition. Conclusion. HPCs have a marked effect on HCC cells in vitro and appear to stimulate the growth and malignant potential of experimental HCC tumors.

Key Words::

• Epithelial-mesenchymal transition
• hepatic progenitor cell
• hepatocellular carcinoma
• liver regeneration

Acknowledgments

The authors sincerely thank Dr George Michalopoulos (University of Pittsburgh) and Professor William B. Coleman (University of North Carolina) for the generous contribution of JM1 and WB-F344 cells. They also thank Mrs Helga Grøsvik and Dr Lene Wierød (Department of Pathology, Oslo University Hospital) for their kind technical supports.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.