Casper Zebrafish as a Model Organism for Cancer Research

Cancer remains a disease area that attracts a substantial amount of research and funding each year. Over the next two decades, current statistics from the World Health Organisation predict a 70% increase in the number of new cancer cases worldwide (1). This high incidence of cancer in the modern age means that most individuals will know several people affected by the disease. Cancer is the cause of greater than 1 in 4 deaths in the UK, and a BBC survey revealed it to be the leading fear of the general public; more so than debt, knife crime and unemployment (2).In order to reduce or eradicate cancer, further research is required.

Various animal models are used in scientific research to study the dynamics of cancer and to improve understanding of malignant cell biology. Although rodents remain the most commonly used animals in cancer research, rabbits, dogs, cats, and fish are also utilised.

The zebrafish, Danio rerio, has proven to be a powerful model organism in the field of developmental biology, and its similarities to humans in terms of genetics and common vertebrate organ systems have shown to be beneficial in a number of fields of biology. The zebrafish has also been used as a model for neurodegenerative disease, cardiovascular disease and diabetes and its rise as a scientific model organism over the past 20 years cannot be ignored. There are a number of reasons underlying why the zebrafish is an important model organism, including their small size, cheap maintenance, and rapid development. In addition, hundreds of embryos may be produced weekly through the breeding of one pair of adults, each with the potential to become mature larvae that are capable of feeding within 5 days of fertilisation. The large size of the embryos mean that they are easy to work with, and their transparency enables visualisation of development; another valuable feature in research of any model organism. The zebrafish genome sequence has also been well-established through large scale genetic screenings, and genetic manipulation is possible by introducing transgenes into the germline through transposon transgenesis, or by gene knockdown using morpholinos, oligonucleotides capable of binding and inhibiting normal mRNA transcript processing.

In 2008, a mutated strain of the zebrafish was produced in Boston and named ‘Casper’, due to its ghostly appearance. The mutant differs from the wild type strain of the fish due to the fact it retains its transparency from the embryonic stage all the way through to adult life (3). The transgenic zebrafish remain transparent due to the knockout of two genes responsible for pigmentation in the skin; nacre and roy orbison. The newly synthesised strain is expected to allow insights into cancer biology that no other model has previously allowed.

The property of transparency being in adult zebrafish allows observation of tumour formation in vivo. This is an incredibly useful tool for studying cancer progression in a living organism. Through implanting fluorescent melanomas into the Casper strain, researchers have been able to witness tumour growth and metastasis in real time (4)(5), and through this method, White et al were able to observe that the transplanted tumour cells had migrated from the abdomen to the kidney. This is a first for in vivo observation of tumours in living adult zebrafish. In vivo observation of tumours can lead to eye-opening discoveries which will aid the understanding of how cancers spread and act in affected individuals, and has been a huge step forward from in vitro analyses. Use of genetic testing in Casper to identify the effects caused by multiple genomic alterations known in human cancers would be a valuable application in cancer research with the potential to improve our understanding of tumour formation.

The transparent adult zebrafish strain, Casper, serves as the ideal combination of sensitivity and single cell resolution for in vivo stem cell analyses. Being a vertebrate model with strong similarities to humans in many respects, and being amenable to genetic techniques, means that future study using Casper could highlight the dynamics of cancer tumour cells that otherwise would not be viewable in alternative opaque models or in vitro methods. Increased funding for zebrafish cancer research  is necessary in order to facilitate unbiased genetic and chemical screens.  Current experimentation using mouse models require termination of the animal to visualise any effect, however, the transparent nature of the Casper mutant eliminates this problem (6). Overall, the Casper mutant proves to be an exciting prospect in terms of future cancer biology research.

By Thomas Sheard, 4th year BSc Biological Sciences (Ind)

References:

(1) World Health Organisation. http://www.who.int/cancer/en/
(2) BBC. Cancer ‘is nation’s biggest fear’    http://www.bbc.co.uk/news/health-11937305
(3) White, R., et al. (2008). Transparent adult zebrafish as a tool for in vivo transplantation. Cell Stem Cell, ;2(2):183-9. doi: 10.1016/j.stem.2007.11.002
(4) White, R., et al. (2013). Zebrafish cancer: the state of the art and the path forward. Nature Reviews Cancer; 13,624–636 doi:10.1038/nrc3589
(5) Veinotte, C., et al. (2014). Hooking the big one: the potential of zebrafish xenotransplantation to reform cancer drug screening in the genomic era. Dis. Model. Mech. doi: 10.1242/dmm.015784 vol. 7 no. 7745-754
(6) The Scientist. (2013) Models of Transparency. http://www.the-scientist.com/?articles.view/articleNo/34834/title/Models-of-Transparency/

Figures:
1 – Alamy stock photo
2 – White, R., et al. (2008). Transparent adult zebrafish as a tool for in vivo transplantation. Cell Stem Cell; 2(2):183-9. doi: 10.1016/j.stem.2007.11.002
3 – White, R., et al. (2013). Zebrafish cancer: the state of the art and the path forward. Nature Reviews Cancer; 13,624–636 doi:10.1038/nrc3589

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