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Zebrafish cancer: the state of the art and the path forward

Nature Reviews Cancer volume 13, pages 624–636 (2013)Cite this article

Subjects

Key Points

  • Zebrafish develop cancer that is histologically and genetically similar to that of humans and it can develop spontaneously, after mutagen exposure or through transgenesis.

  • Large-scale transgenesis using hundreds to thousands of embryos per day allows for deep functional characterization of genetic abnormalities that have been discovered in human cancer studies, such as The Cancer Genome Atlas.

  • Chemical screens have successfully been used in zebrafish embryos to find molecules and pathways that are directly relevant to human malignancy, and drugs from these screens have entered clinical trials in patients.

  • Large-scale forward genetic screens offer a unique opportunity to identify cancer phenotypes in an unbiased manner.

  • Transparent embryos and adults allows for in vivo visualization of cancer growth and progression at single-cell resolution.

  • Xenotransplantation of human cancer cells into zebrafish larvae provides opportunities for personalized cancer screens.

  • Major areas of growth in the coming decade include modelling multigenic changes in cancer, epigenetics and the dissection of metastasis.

Abstract

The zebrafish is a recent addition to animal models of human cancer, and studies using this model are rapidly contributing major insights. Zebrafish develop cancer spontaneously, after mutagen exposure and through transgenesis. The tumours resemble human cancers at the histological, gene expression and genomic levels. The ability to carry out in vivo imaging, chemical and genetic screens, and high-throughput transgenesis offers a unique opportunity to functionally characterize the cancer genome. Moreover, increasingly sophisticated modelling of combinations of genetic and epigenetic alterations will allow the zebrafish to complement what can be achieved in other models, such as mouse and human cell culture systems.

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Figure 1: Zebrafish anatomy.
Figure 2: Studying cancer in the zebrafish.
Figure 3: Cross-species oncogenomics provides a powerful way to identify highly evolutionarily conserved events in tumorigenesis.
Figure 4: Transplantation tools available in the zebrafish.
Figure 5: Chemical screening in the zebrafish.

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Authors and Affiliations

  1. Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA

    Richard White

  2. Weill-Cornell Medical College, New York, 10021, New York, USA

    Richard White

  3. Children's Hospital Boston, Boston, Massachusetts, USA

    Kristin Rose & Leonard Zon

  4. Howard Hughes Medical Institute, Boston, 02115, Massachusetts, USA

    Kristin Rose & Leonard Zon

  5. Harvard Medical School, Boston, Massachusetts, USA

    Kristin Rose & Leonard Zon

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  1. Richard White
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  2. Kristin Rose
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  3. Leonard Zon
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Correspondence to Richard White or Leonard Zon.

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Competing interests

L.Z. is a founder and stockholder of Fate Therapeutics, and a founder and stockholder of Scholar Rock Inc., and a scientific adviser for Stemgent. R.W. and K.R. declare no competing financial interests.

PowerPoint slides

Glossary

Forward genetic screens

An approach in which germline mutations are induced by mutagens such as ethylnitrosourea and offspring are scored for phenotype of interest. The causal mutation is then identified in mutants with interesting phenotypes.

GISTIC

(Genomic identification of significant targets in cancer). An algorithm for the identification of copy number gains and losses in human cancer, using genome-wide data such as high-density single nucleotide polymorphism arrays.

Caudal haematopoietic tissue

(CHT). A region of the zebrafish embryo that acts as an intermediate site of embryonic blood development.

TILLING

(Targeting induced local lesions in genomes). A technique to identify specific mutations in a gene of interest. Unbiased mutagenesis of the genome using ethylnitrosourea is carried out, followed by PCR-based sequencing of the region of interest to identify zebrafish with the preferred mutation.

Li–Fraumeni syndrome

An autosomal-dominant condition caused by an inherited mutation in p53 that renders humans highly susceptible to a number of cancers, including breast cancer, leukaemia and sarcoma.

CRISPR–Cas

Clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated (Cas).

miR-30-based approaches

A technique for improving the efficiency of in vivo RNA interference. A short hairpin RNA against a gene of interest is embedded within an endogenous microRNA-30 (miR-30) backbone, which allows for high-level expression from RNA polymerase II promoters.

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White, R., Rose, K. & Zon, L. Zebrafish cancer: the state of the art and the path forward. Nat Rev Cancer 13, 624–636 (2013). https://doi.org/10.1038/nrc3589

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  • DOI: https://doi.org/10.1038/nrc3589

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