| Summary: | Background. Liver cancer is the 3rd commonest cause of cancer death worldwide. Understanding the mechanisms of hepatocarcinogenesis is vital for developing more effective treatments. Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (HCC) and increased translocation of gut bacteria is believed to exacerbate this inflammatory condition. Toll-like receptors (TLRs) play a crucial role in immunity against microbial pathogens and recent evidence suggests they may be important in pathogenesis of chronic liver disease. The aim of this thesis was to explore the role of TLRs in the pathogenesis of HCC. Materials & Methods: Tissue microarrays obtained from patients with cirrhosis, viral hepatitis and HCC were stained with for TLR4, TLR7 and TLR9 and the data were validated in actual patient samples. The role of gut translocation was explored in an animal model of HCC using diethylnitrosamine (DEN) and nitrosomorpholine (NMOR) after treatment with Norfloxacin. Proliferation of HCC cell lines were studied after stimulation (Imiquimod and CpG-ODN) and inhibition of TLR7 and TLR9 (IRS 954) and chloroquine. The effect of these interventions was confirmed in the DEN and NMOR and, a xenograft model. The studies were extended to determine their effect in cholangiocarcinoma. Results: TLR7 and TLR9 but not TLR4 were up regulated in HCC tissue and gut decontamination with Norfloxacin did not prevent HCC development but reduced liver fibrosis. TLR7 stimulation increased cell proliferation of HuH7 cells significantly and inhibition of TLR7 and TLR9 using IRS or chloroquine resulted in significant inhibition. TLR7 and TLR9 inhibition using IRS 954 and chloroquine reduced tumour growth in xenograft models and, chloroquine also decreased liver fibrosis and tumour growth in the DEN and NMOR model. These beneficial effects were also observed in cholangiocarcinoma. Conclusion: In conclusion, these data suggest that inhibiting TLR7 and TLR9 and, using chloroquine could be potential novel therapeutic strategies for the prevention and the progression of primary liver cancers in susceptible patients.
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