The zebrafish as a model for cancer

Abstract

For the last three decades significant parts of national science budgets, and international and private funding worldwide, have been dedicated to cancer research. This has resulted in a number of important scientific findings. Studies in tissue culture have multiplied our knowledge of cancer cell pathophysiology, mechanisms of transformation and strategies of survival of cancer cells, revealing therapeutically exploitable differences to normal cells. Rodent animal models have provided important insights on the developmental biology of cancer cells and on host responses to the transformed cells. However, the rate of death from some malignancies is still high, and the incidence of cancer is increasing in the western hemisphere. Alternative animal models are needed, where cancer cell biology, developmental biology and treatment can be studied in an integrated way. The zebrafish offers a number of features, such as its rapid development, tractable genetics, suitability for in vivo imaging and chemical screening, that make it an attractive model to cancer researchers. This Primer will provide a synopsis of the different cancer models generated by the zebrafish community to date. It will discuss the use of these models to further our understanding of the mechanisms of cancer development, and to promote drug discovery. The article was inspired by a workshop on the topic held in July 2009 in Spoleto, Italy, where a number of new zebrafish cancer models were presented. The overarching goal of the article is aimed at raising the awareness of basic researchers, as well as clinicians, to the versatility of this emerging alternative animal model of cancer.

Fig. 1.

The use of a zebrafish melanoma model to detect immune responses. (A) A juvenile kita:GFP-HRASV12 zebrafish developing a melanocytic lesion on the tail fin. (B) The fish is also transgenic for LysC:RFP (Hall et al., 2007), which marks a subpopulation of macrophages. (C,D) Red macrophages attack and destroy a GFP-HRASV12 transformed cell. Bar, 100 μm (A); 40 μm (B); 10 μm (C,D).

Fig. 2.

The generation of reference transcriptomes associated with specific cancer models. (A) Cross comparison between cancer transcriptomes of different stages within the same genetic model, further compared with different genetic models of the same tumor, will produce stage- and cancer-specific signatures. The transcriptome of each genetic model can be studied at precise stages (rectangles) and subjected to cross comparisons (Venn diagrams) to generate stage-specific signatures (the non-overlapping parts of the colored circles). This process can be repeated for any number of cancer models, even from different species. (B) These signatures will help to assign transcriptomes from unknown-stage human cancers to a specific class. In the left panels, the different shades of colored shapes identify stage-specific transcriptomes derived from animal models that, thanks to the large number examined, allow a single grade-specific signature (intensely-colored rectangles) to be derived. In the right panels, different transcriptomes from human cancer samples are assessed and assigned to a specific group. (C) A smaller number of ‘predictor genes’ can be derived from these cross-species comparisons, which can help to stratify patients to the correct cohort for prognosis and therapy follow-up.