Surgery (Austin & Northern Health) - Theses

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    The role of the renin-angiotensin system in liver regeneration and colorectal cancer liver metastases
    KOH, SHIR LIN ( 2012)
    Background: Colorectal cancer (CRC) is the second most common cause of cancer related death in Australia with over 4700 deaths reported annually. CRC liver metastasis (CRCLM) contributes to over 70% of the disease mortality. While unresected patients rarely survive beyond 2 years, partial hepatectomy (PH) improves their survival to 25%-60% at 5 years. Blockade of the renin-angiotensin system(RAS) has been shown to enhance liver regeneration and, separately, to inhibit CRCLM. Targeting the RAS may offer a unique synergistic anti-cancer therapy by inhibiting CRCLM tumour growth while simultaneously enhancing liver regeneration following PH. Aim: This study investigated the expression of the RAS during liver regeneration and in CRCLM. The effects of RAS blockade on liver regeneration and CRCLM in the regenerating liver were determined to investigate its potential benefits as a therapeutic avenue for CRCLM patients. Methods: Male CBA mice (10-12 weeks) were used in this study. After 70% partial hepatectomy (PH) alone, captopril (750mg/kg) or saline (control), were administered intraperitoneally on a daily basis until the endpoints (days 1, 2, 4, 6 and 8 post-surgery). A mouse model of CRCLM in the regenerating liver was developed. Mice induced with CRCLM and subjected to 70% PH were treated with captopril (250mg/kg) daily until the endpoints (days 2, 6, 16 and 21). At study endpoints, liver regeneration was assessed by measuring the liver-to-body weight ratio. CRCLM tumour burden (percentage of liver metastases) was calculated using total liver and tumour volumes using quantitative stereology. Liver function tests were performed on mouse serum collected from days 2 and 6. The expression of the RAS components, cell proliferation, apoptosis, hepatic stellate cells (HSC) and liver endothelial cell densities, matrix metalloproteinase (MMP)-9, transforming growth factor (TGF)-β were quantified. Statistical analyses were performed using 2-sample independent T-test, one-way ANOVA with post-hoc analysis, or Kruskal Wallis followed by Mann-Whitney U tests as appropriate (SPSS v.18). P-value of <0.05 was considered statistically significant. Results: Captopril significantly inhibited CRCLM tumour growth and increased tumour cell apoptosis in the regenerating liver at day 21. Captopril also enhanced early liver regeneration and this was associated with an increase in hepatocyte proliferation at 6 hours after PH as well as an increase in HSC density and MMP-9 levels 2 days after PH. The decrease in hepatocyte proliferation at day 2 was transient. By day 4 onwards there was no significant difference between control and treated livers. Captopril also decreased the hepatocyte injury marker, alanine transaminase. The ability of captopril to increase human hepatocyte proliferation was confirmed in vitro. The RAS was expressed in the liver and tumours during liver regeneration and tumour growth phases. Liver and tumour differed in their RAS expression; tumour AT1R expression levels were lower than normal liver, while tumour MasR and AT2R levels were upregulated during cancer progression. Conclusion: This thesis showed a tumour-specific RAS expression which could be targeted to inhibit tumour growth while allowing the liver to regenerate following PH. This is supporting by my findings that RAS blockade with captopril following PH was associated with a reduction in CRCLM tumour growth without impairing liver regeneration. Thus, captopril may offer a new avenue to improve CRCLM patient outcomes by inhibiting tumour growth whilst enhancing the early stage of liver regeneration.