Post hepatectomy liver regeneration stimulates tumour progression in the residual liver

Abstract

Introduction: Worldwide, colorectal cancer (CRC) is the second commonest cause of cancer death. Advances in primary cancer treatment have led to the emergence of metastases as the major cause of cancer deaths. Intrahepatic recurrence of CRLM occurs in 40% of patients who undergo hepatectomy and the majority of recurrences occur within 6months of liver resection. This supports the hypothesis that post-hepatectomy liver regeneration (LR) paradoxically drives tumour progression. We aimed to investigate this and the underlying mechanisms. Method: Male CBA mice underwent CRLM tumour induction and were divided in two groups: with 70% partial hepatectomy (PH) and without (control). Three regions of mice liver tissue were isolated; tumour, peritumoural stromal tissue and normal liver tissue. Liver tissue was analysed for markers of cellular proliferation (Ki67) and epithelial-to-mesenchymal transition (EMT). In vitro studies utilising a mouse colorectal cancer cell line were carried out to investigate the effect of serum from liver regenerating mice on the proliferation of tumour cells and their expression of EMT markers. Result: Tumour burden was significantly higher in the PH group compared to the control group (p=0.040). Ki67 staining was significantly greater in both the hepatocytes and the tumours cells in the PH group compared to the control group (p=0.008 and p=0.038 respectively). Markers of EMT including Zeb-1 and Vimentin were expressed differentially between the normal liver, stroma and tumour. Post hepatectomy vimentin staining was significantly upregulated in the liver, compared to tumour induction alone (p=0.01[MP1] 0). Proteomic analysis of three regions revealed that protein expression differs between regions and several proteins associated with key signalling pathways such as the Wnt-ß-catenin were identified. In-vitro studies demonstrated that LR serum stimulated significantly greater tumour growth than control (p=<0.001 at 72hours). Conclusion: Partial hepatectomy drives tumour progression and one mechanism for this appears to be through the up-regulation of EMT pathways.