Professor Narci Teoh, School of Clinical Medicine, ANU Medical School and Gastroenterology and Hepatology Research Unit, The Canberra Hospital.
Hepatocellular carcinoma (HCC) is a fatal malignancy that ranks amongst the top 3 causes of cancer deaths worldwide. While the main risk factors for HCC are well known, such as hepatitis B and C virus infection, alcohol dependence and increasingly, obesity and type 2 diabetes, the key pathogenic and molecular mechanisms underlying liver carcinogenesis remain poorly defined. Research into HCC (or any cancer) requires appropriate and relevant models which incorporate the use of risk factors associated with tumour development, and those which accurately mimic the natural history, molecular and pathobiological characteristics of HCC, as well as the tissue microenvironment in which it arises. ‘Hepatoma’ cancer cell lines, derived from human or animal HCCs, enable mechanistic studies into genetic alterations causing abnormalities in hepatocyte proliferative and cell death signalling pathways, malignant transformation and the acquisition of metastatic potential. While the choice of using cell lines reflect their ease of availability and convenience, they bear little resemblance and relevance biologically to HCC in situ. In contrast, in vivo models of HCC better reflect human disease but vary in their derivation, establishment and ability to recapitulate the multi-step process of liver carcinogenesis, histopathology, the cirrhotic environment in which majority of human HCCs arise, as well as the molecular features of such tumours. This lecture will critically review a suite of different experimental models commonly utilised in liver cancer research, in particular the advantages and pitfalls underlying xenograft models, syngeneic animal model systems, carcinogen-induced rodent models, hepadnaviral-induced HCCs as well as ‘classical’ transgenic and tetracycline-regulated transgenic approaches. Selecting the ‘best-fit’ models to elucidate the pathogenesis of HCC and ultimately, to test the efficacy of therapies against HCC is of critical importance.