Models for Liver Cancer

Abstract

Primary liver tumours include hepatocellular carcinomas (HCCs), cholangiocarcinomas, and hepatoblastomas. HCC is the most frequent liver tumour, whose development is preceded, both in humans and rodents, by the appearance in the liver of foci of altered hepatocytes (FAHs) and dysplastic nodules. Bipotential hepatic progenitor cells (HPCs), which may differentiate into hepatocytes or cholangiocytes, are liver tumour precursors. Several rodent models have been developed to study the aetiology, evolution, and pathogenesis of preneoplastic and neoplastic liver lesions. They include the woodchuck hepatitis model, chemical models in which hepatocyte initiation by a carcinogen is followed by a growth stimulus inducing clonal expansion of initiated cells, diet‐linked models based on induction of methyl donor deficiency, and transgenic/knockout models, particularly useful to study in vivo role(s) of genes favouring or suppressing neoplastic cell growth. Furthermore, in vitro growing liver tumour cell lines have been used to study the role of single genes or signal transduction pathways, the effect of inhibitor compounds and genome engineering on tumour growth, and gene expression profiles. Transplants of in vitro growing cells are currently used for chemopreventive and therapeutic approaches to hepatocarcinogenesis. Animal models of liver cancer allowed investigation of the molecular alterations involved in early stages and in the progression phase of hepatocarcinogenesis, thus evidencing the interspecies commonalties of the basic mechanisms of hepatocarcinogenesis, and strongly contributing to understanding the molecular bases of the disease. Finally, animal models allowed investigation of genetic predisposition to liver cancer and contributed to map predisposition genes, understanding the genetic model, and some effector mechanisms of cancer modifier genes.

Experimental models of hepatocellular carcinoma

“…HCC is preceded in both rodents and humans by the development of premalignant lesions including foci of altered hepatocytes and dysplastic nodules, which exhibit a higher risk of malignant evolution than normal cells [40,41]. Various genetic alterations and exposures to chemical carcinogens have been studied in animals in order to recapitulate the phenotypic, biological, and molecular events that occur during this transformation.…”

“…In most organs, metallonein-driven over-expression of TGF-a causes epithelial hyperplasia [41]. In liver and breast tissue, the phenotype extends to neoplastic transformation.…”

“…Fundamental to our understanding of cancer biology have been models simulating loss of tumor suppressors p53 and Retinoblastoma (Rb), key regulators of cell cycling and frequent targets of carcinogens. There is a large body of evidence indicating a pivotal role for cell cycle deregulation during hepatocarcinogenesis [41]. Tumor suppressor p53 acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, to apoptosis, or to cellular senescence.…”

“…Transcriptional activation of IGF2 has been demonstrated in HCCs arising in HBV-associated human samples [112] and in HBV transgenic mice [41]. To investigate whether IGF-2 has a promoter role in a slowly developing HCC model, TGFa transgenic mice were crossed with IGF-2 hemizygous knockout mice containing either only one maternal allele or two alleles.…”

Experimental models of hepatocellular carcinoma: developments and evolution

“…Choline-deWcient and methionine-low diet administered over 2 weeks periods induce rapid liver cell death (Feo 2007). The feeding of a Choline-deWcient and methioninelow diet to rats accelerated liver cancer development in association with the administration of DENA, azaserine or AAF.…”