Hepatic Progenitor Cells Facilitate the Growth and Malignant Potential of Experimental Hepatocellular Carcinoma after Surgery

Abstract

Liver regeneration may influence the kinetics of tumor growth and thereby contribute to recurrence. Recent experimental findings indicate that large liver resections can mobilize peripheral hematopoietic stem cells into the liver that differentiate into hepatic progenitor cells (HPCs). The aim of this project was to explore how activation of HPCs following partial hepatectomy affects growth and malignant development of experimental hepatocellular carcinoma (HCC) in vivo and to study the effect of HPCs on hepatoma cells in vitro. Varying grades of hepatectomy (0%, 30% and 70%) with concomitant implantation of hepatoma cells in the remnant liver were performed in rats. HPC activation was verified by double immunofluorescence staining for cytokeratin 19 and αFP/CD133. The in vitro effect of HPCs (WB-F344) on hepatoma cells (JM1) was investigated by co-culturing technique, and proliferation rate, sensitivity to Doxorubicin and expression of invasive factors were assessed. The in vivo effect of HPCs on tumor growth was tested in 3 groups of rats undergoing 70% hepatectomy and implantation of JM1 hepatoma cells (wild type, wild type co-cultured with HPC and wild type + HPC transplantation). Activation of HPCs in-vivo was demonstrated after surgery. Co-cultured JM1 cells showed enhanced malignant properties by increased IC50 after Doxorubicin exposure, and increased expression of tumor biological markers (Figures 1–3). Animals with JM1 tumors and concomitant HPC transplantation or co-culture displayed markedly increased tumor size, metastasis (Table 1) and enhanced expressions of Cyclin D1 and MMP9.[Figure 1][Figure 2][Figure 3]Conclusion: HPC activation is associated with enhanced tumor development and metastasis. Tumor cells co-cultured with HPCs display enhanced invasive capability and stem-like expression pattern. The results suggest that HPC activation may facilitate HCC growth after surgery.