Inducible Liver Cancer Models in Transgenic Zebrafish to Investigate Cancer Biology

SIMPLE SUMMARY: Primary liver cancer ranks amongst the top ten cancers in frequency and mortality, with its global prevalence continuing to increase. Chemotherapy response remains poor and many therapies result in adverse side effects. The use of transgenic animal models that have high disease reproducibility provides opportunities to study cancer events that are difficult to study in human patients. Other than well-established mouse models in cancer research, now there is an increasing interest in using zebrafish to model various cancers. This review summarises the various oncogene transgenic zebrafish models for hepatocellular carcinoma (HCC) our laboratory has established, and the subsequent findings about liver cancer biology by using these transgenic models. In particular, most of our transgenic models employed chemically induced oncogene expression, allowing for temporal control and study of tumour initiation and regression. Investigation into these models reveals activation of tumorigenic pathways, inflammation, male-bias severity and skeletal muscle-wasting, characteristic of human HCC. Some of the models are also useful in screening for novel anti-metastatic drugs and evaluating the tumorigenic ability of environmental toxicants. The findings presented here demonstrate the utility of the zebrafish models for the further investigation of cancer biology and the development of novel and improved therapies. ABSTRACT: Primary liver cancer is one of the most prevalent and deadly cancers, which incidence continues to increase while treatment response remains poor; thus, in-depth understanding of tumour events is necessary to develop more effective therapies. Animal models for liver cancer are powerful tools to reach this goal. Over the past decade, our laboratory has established multiple oncogene transgenic zebrafish lines that can be robustly induced to develop liver cancer. Histological, transcriptomic and molecular analyses validate the use of these transgenic zebrafish as experimental models for liver cancer. In this review, we provide a comprehensive summary of our findings with these inducible zebrafish liver cancer models in tumour initiation, oncogene addiction, tumour microenvironment, gender disparity, cancer cachexia, drug screening and others. Induced oncogene expression causes a rapid change of the tumour microenvironment such as inflammatory responses, increased vascularisation and rapid hepatic growth. In several models, histologically-proven carcinoma can be induced within one week of chemical inducer administration. Interestingly, the induced liver tumours show the ability to regress when the transgenic oncogene is suppressed by the withdrawal of the chemical inducer. Like human liver cancer, there is a strong bias of liver cancer severity in male zebrafish. After long-term tumour progression, liver cancer-bearing zebrafish also show symptoms of cancer cachexia such as muscle-wasting. In addition, the zebrafish models have been used to screen for anti-metastasis drugs as well as to evaluate environmental toxicants in carcinogenesis. These findings demonstrated that these inducible zebrafish liver cancer models provide rapid and convenient experimental tools for further investigation of fundamental cancer biology, with the potential for the discovery of new therapeutic approaches.