Mouse models for liver cancer

Abstract

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer is the third leading cause of cancer-related cell death in human and the fifth in women worldwide. The incidence of HCC is increasing despite progress in identifying risk factors, understanding disease etiology and developing anti-viral strategies. Therapeutic options are limited and survival after diagnosis is poor. Therefore, better preventive, diagnostic and therapeutic tools are urgently needed, in particular given the increased contribution from systemic metabolic disease to HCC incidence worldwide. In the last three decades, technological advances have facilitated the generation of genetically engineered mouse models (GEMMs) to mimic the alterations frequently observed in human cancers or to conduct intervention studies and assess the relevance of candidate gene networks in tumor establishment, progression and maintenance. Because these studies allow molecular and cellular manipulations impossible to perform in patients, GEMMs have improved our understanding of this complex disease and represent a source of great potential for mechanism-based therapy development. In this review, we provide an overview of the current state of HCC modeling in the mouse, highlighting successes, current challenges and future opportunities.

Protective effect of yellow tea extract on N-nitrosodiethylamine-induced liver carcinogenesis

“…These results suggest that yellow tea may protect the liver against damage induced by NDEA. The hepatoprotective effect of yellow tea in NDEA-challenged rats might be related to its high antioxidant activity, which is in agreement with current knowledge concerning NDEA biotransformation that requires oxygen-dependent metabolic activation by CYP2E1 and the consequent accumulation of ROS and DNA damage (Kang et al 2007;Bakiri & Wagner 2013). It has been demonstrated that the reactive metabolites of NDEA and oxygen radical by-products of CYP2E1-catalyzedmetabolic activation induce oxidative stress which leads to carcinogenesis (Arul & Subramanian 2013).…”

N-diethylnitrosamine mouse hepatotoxicity: Time-related effects on histology and oxidative stress

“…DEN exposure, resulted in regionally extensive to diffuse hepatocellular hydropic degeneration and multifocal necrosis, as well as in increased anisokaryosis, binucleated and mitotic hepatocytes, pseudo-nucleoli and apoptosis. These results are according to current knowledge concerning biotransformation of chemical carcinogens such as DEN, which requires oxygen-dependent metabolic activation by cytochrome P450 (CYP) system, with sub-sequent accumulation of ROS and DNA damage (Kang et al, 2007;Bakiri and Wagner, 2013).…”

“…Increased ROS production is a result of several environment distresses, resulting in a stressful condition, inflicting direct damage to macromolecules, such as lipids, proteins and nucleic acids, and leading ultimately to carcinogenesis. Generation of ROS is associated to endogenous processes -normal aerobic cellular metabolism, and to exogenous processes, such as xenobiotic chemical exposure and toxicity, namely nitrosamine (Klaunig and Kamendulis, 2004;Del Rio et al, 1977;Bakiri and Wagner, 2013). Our data suggest a DEN influence in the balance of the antioxidant activities towards ROS.…”

“…29 and 36 weeks post-exposure) showed chronic lesions that affected normal hepatic architecture. Hepatocellular adenomas were identified at T4; how-ever, histological evaluation did not support positive hepatocellular carcinoma identification, probably due to the time of DEN administration (mice older than 2 weeks) without any promoter agent (Bakiri and Wagner, 2013;De Minicis et al, 2013).…”

MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches

“…185 Compared with human HCC, genetically modified mouse models generally develop HCC without the development of liver cirrhosis. However, this condition is present in 480% of human HCC cases.…”