Making Waves in Cancer Research: New Models in the Zebrafish

Abstract

The zebrafish (Danio rerio) has proven to be a powerful vertebrate model system for the genetic analysis of developmental pathways and is only beginning to be exploited as a model for human disease and clinical research. The attributes that have led to the emergence of the zebrafish as a preeminent embryological model, including its capacity for forward and reverse genetic analyses, provides a unique opportunity to uncover novel insights into the molecular genetics of cancer. Some of the advantages of the zebrafish animal model system include fecundity, with each female capable of laying 200-300 eggs per week, external fertilization that permits manipulation of embryos ex utero, and rapid development of optically clear embryos, which allows the direct observation of developing internal organs and tissues in vivo. The zebrafish is amenable to transgenic and both forward and reverse genetic strategies that can be used to identify or generate zebrafish models of different types of cancer and may also present significant advantages for the discovery of tumor suppressor genes that promote tumorigenesis when mutationally inactivated. Importantly, the transparency and accessibility of the zebrafish embryo allows the unprecedented direct analysis of pathologic processes in vivo, including neoplastic cell transformation and tumorigenic progression. Ultimately, high-throughput modifier screens based on zebrafish cancer models can lead to the identification of chemicals or genes involved in the suppression or prevention of the malignant phenotype. The identification of small molecules or gene products through such screens will serve as ideal entry points for novel drug development for the treatment of cancer. This review focuses on the current technology that takes advantage of the zebrafish model system to further our understanding of the genetic basis of cancer and its treatment.

Catch of the day: zebrafish as a human cancer model

“…Water-soluble carcinogens can be added directly to the fish water and a number of chemical compounds that are carcinogenic in mammals induce tumor formation in zebrafish (Amatruda et al, 2002;Berghmans et al, 2005a;Goessling et al, 2007a, b). Exposure to dimethylbenzanthracene, ethylnitrosourea, N-methyl-N-nitro-Nnitrosoguanidine, diethylnitrosamine results in a variety of tumors in zebrafish or medaka (Oryzias latipes) (Okihiro and Hinton, 1999;Beckwith et al, 2000;Spitsbergen et al, 2000a, b;Mizgireuv et al, 2004;Lam and Gong, 2006;Mizgireuv and Revskoy, 2006).…”

“…While it has been known for more than a century that teleost fish can develop tumors spontaneously or in response to various chemical carcinogens, it has not been until recently that this small creature has received so much attention by cancer researchers (Amatruda et al, 2002;Smolowitz et al, 2002;Stern and Zon, 2003;Berghmans et al, 2005a;Goessling et al, 2007a). This is largely due to the development of fish lines harboring oncogenic transgenes and their amenability to genetic and pharmacological testing.…”

“…This is largely due to the development of fish lines harboring oncogenic transgenes and their amenability to genetic and pharmacological testing. Cancer progression in these animals recapitulates many aspects of human disease and opens the door for studies to identify genetic and chemical modifiers of cancer (Amatruda et al, 2002;Smolowitz et al, 2002;Stern and Zon, 2003;Berghmans et al, 2005a;Goessling et al, 2007a;Kari et al, 2007). The attention has been further fueled by the development of xenograft models that allow the propagation and visualization of human cancer cells engrafted in optically transparent zebrafish (Haldi et al, 2005;Lee et al, 2005;Topczewska et al, 2006;Nicoli et al, 2007;Stoletov et al, 2007).…”

“…Finally, zebrafish have many attributes that cancer researchers find attractive. Compared to mice, zebrafish require minimal care and are cost effective to maintain in the laboratory (Amatruda et al, 2002;Smolowitz et al, 2002;Stern and Zon, 2003;Berghmans et al, 2005a;Goessling et al, 2007a;Kari et al, 2007). A pair of adult fish produces several hundred fertilized eggs a week.…”

“…A complete sequence of the zebrafish genome is available and many human cancer genes are conserved structurally and functionally in zebrafish (http://www.ncbi.nlm.nih.gov/genome/guide/zebrafish). Zebrafish genetics is easily manipulated with numerous mutant or tissue-specific transgenic fish lines available (Amatruda et al, 2002;Smolowitz et al, 2002;Stern and Zon, 2003;Berghmans et al, 2005a;Beis and Stainier, 2006;Goessling et al, 2007a;Kari et al, 2007). Zebrafish can also efficiently absorb small molecular weight compounds directly from water which makes this organism especially appealing for screening anticancer agents (Parng et al, 2002;Kari et al, 2007).…”