Heat stress and thermal ablation induce local expression of nerve growth factor inducible (VGF) in hepatocytes and hepatocellular carcinoma: pre-clinical and clinical studies.

Purpose: To test the hypothesis that heat stress and hepatic thermal ablation induce nerve growth factor inducible (VGF) and to determine intrahepatic versus systemic VGF expression induced by thermal ablation in vivo and in patients. Materials and Methods: Hepatocytes and HCC cells were subjected to moderate(45°C) or physiologic(37°C) heat stress for 10 minutes and assessed for VGF expression at 0-72 hours post-heat stress(N≥3 experiments). Orthotopic N1S1 HCC bearing rats were randomized to sham or laser-thermal ablation (3 wattsx90s) and liver/serum were harvested at 0-7 days postablation for analysis of VGF expression(N≥6 per group). Serum was collected from patients undergoing thermal ablation for HCC(N=16) at baseline, 3-6 and 18-24 hours post-ablation and analyzed for VGF expression. Data were analyzed using ordinary or repeated measures one-way analysis of variance, and post-hoc pairwise comparison with Dunnett's test. Results: Moderate heat stress induced time-dependent VGF mRNA (3-15-fold; p<0.04) and protein expression and secretion(3.1-3.3-fold; p<0.05). Thermal ablation induced VGF expression at the hepatic ablation margin at 1 and 3 days post ablation but not remote from the ablation zone or distant intrahepatic lobe There was no detectable serum VGF following hepatic thermal ablation in rats and no increase in serum VGF following HCC thermal ablation in patients at 3-6 and 18-24 hours post-ablation compared to baseline(0.71-fold and 0.63-fold, p=0.27 and p=0.16, respectively). Conclusion: Moderate heat stress induces expression and secretion of VGF in HCC cells and hepatocytes in vitro and thermal ablation induces local intrahepatic but not distant intrahepatic or systemic VGF expression in vivo.