Animal Models: A Useful Tool to Unveil Metabolic Changes in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one the most frequent and lethal human cancers. At present, no effective treatment for advanced HCC exist; therefore, the overall prognosis for HCC patients remains dismal. In recent years, a better knowledge of the signaling pathways involved in the regulation of HCC development and progression, has led to the identification of novel potential targets for therapeutic strategies. However, the obtained benefits from current therapeutic options are disappointing. Altered cancer metabolism has become a topic of renewed interest in the last decades, and it has been included among the core hallmarks of cancer. In the light of growing evidence for metabolic reprogramming in cancer, a wide number of experimental animal models have been exploited to study metabolic changes characterizing HCC development and progression and to further expand our knowledge of this tumor. In the present review, we discuss several rodent models of hepatocarcinogenesis, that contributed to elucidate the metabolic profile of HCC and the implications of these changes in modulating the aggressiveness of neoplastic cells. We also highlight the apparently contrasting results stemming from different animal models. Finally, we analyze whether these observations could be exploited to improve current therapeutic strategies for HCC.

Keywords: HCC; OXPHOS; PPP; glycolysis; miRNA.

Figure 1

Examples of rat models used for the study of metabolic reprogramming in HCC. DENA: diethylnitrosamine; CMD: choline-devoid methionine-deficient diet; PH: partial hepatectomy; 2-AAF: 2-acetylaminofluorene; PP: Peroxisome Proliferator; PB: Phenobarbital; DHEA: dehydroepiandrosterone; CCl₄: carbon tetrachloride; KO: knockout; Nrf2: nuclear factor, erythroid 2 like 2. The figure has been prepared by adapting BioRender images.

Figure 2

Examples of mouse models used for the study of metabolic reprogramming in HCC. DENA: diethylnitrosamine; PB: phenobarbital; TCPOBOP: 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene; Hk2: hexokinase 2; Pkm2: pyruvate kinase M2; Nrf2: nuclear factor, erythroid 2 like 2; Fasn: fatty acid synthase; Gnmt: glycine N-methyltransferase; IF1: ATPase Inhibitory Factor 1; AKT: protein-kinase B; G6pd: glucose-6-phosphate dehydrogenase; Tkt: transketolase. Hydrodynamic Injection. Cancer cells. The figure has been prepared by adapting BioRender images.

Figure 3

Principal metabolic changes observed in (A) human cirrhosis and HCC, (B) rat cirrhotic liver/preneoplastic lesions, rat HCC, as well as (C) in mouse HCC. The figure has been prepared by adapting BioRender images.

Figure 4

Schematic representation of altered biochemical pathways in rat preneoplastic nodules and HCC (red: up-regulation, green: down-regulation). The figure has been prepared by adapting BioRender images.