Effects of Human Hepatocyte Growth Factor on the Proliferation of Human Hepatocytes and Hepatocellular Carcinoma Cell Lines

Abstract

Background: Hepatocyte growth factor (HGF) has been suggested to initiate both hepatocyte and tumor cell proliferation after partial hepatectomy, thereby supporting local tumor recurrence. The aim of this study was to clarify the role of HGF in the regeneration of human hepatocyte and the growth of residual hepatocellular carcinoma cells after liver resection. Patients/Methods: 36 patients who underwent partial hepatectomy for hepatocellular carcinoma (HCC) or living liver donation have been analyzed for HGF serum levels at day –1 through day 5 following surgery using an enzyme-linked immunosorbent assay. Isolated human hepatocytes and HCC cell lines (Hep 3B, Hep G2) were treated either with recombinant human (rh)-HGF, or sera from the 36 patients in the presence or absence of anti-HGF in order to measure their proliferative capacity using ³H-thymidine incorporation. Results: Basal HGF levels were significantly higher in HCC than in healthy patients (1,573 ± 131 vs. 778 ± 64 pg/ml; p < 0.001), however, the postoperative rise of HGF in healthy patients was higher (9,608 ± 3111 vs. 2,060 ± 148 pg/ml) than in HCC patients. Incubation of human hepatocytes and Hep 3B cells with rh-HGF revealed a dose-dependent increase in DNA synthesis, while anti-HGF partially abolished this effect. Sera from normal and resected HCC patients stimulated DNA synthesis only in human hepatocytes, whereas it was inhibited in HCC cell lines. Conclusion: HGF plays an important role in hepatocyte proliferation but contrary to in vitro results, HGF does not play a major role for the progression of hepatocarcinoma cells in vivo.

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…This receptor tyrosine kinase (RTK) is predominantly expressed on epithelial and endothelial cells and regulates proliferation (Efimova et al, 2004), migration (Monvoisin et al, 1999), cell survival (Suzuki et al, 2000), morphogenesis , angiogenesis (Schmidt et al, 1995), as well as tissue regeneration (Borowiak et al, 2004). Hepatocyte growth factor binding and MET multimerization results in receptor auto-and paraphosphorylation of adaptor proteins (e.g.…”

Liver transplantation for hepatocellular carcinoma from living-donor vs. deceased donor

“…The hypothesized mechanism in experimental studies for the faster tumor progression and the higher recurrence rates in LDLT is that growth factors and cytokines released during rapid regeneration of the partial grafts from the partial graft might contribute to tumor progression and recurrence (5)(6)(7)(8). An ischemic-reperfusion injury facilitated by a small-for-size graft and the rapidly regenerating liver parenchyma in LDLT setting may increase vascular endothelial growth factor expression and angiogenesis, which might accelerate the tumor progression and recurrence.…”

Living vs. deceased-donor liver transplantation for patients with hepatocellular carcinoma

“…The inferior results of LDLT have been attributed to growth factors and cytokines released during acute graft injury, and subsequent graft regeneration resulting from the small-for-size graft in LDLT (36)(37)(38)(39) OS, overall survival; RFS, recurrent-free survival; RR, recurrence rate; A2ALL, Adult-to-Adult Living Donor Liver transplantation Cohort Study; N.S., not significant.…”