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Published Online:https://doi.org/10.2217/fon.11.137

The small vertebrate, zebrafish, has generated a big wave in current biomedical research. In the early experiments of carcinogen treatment, it has been found that the induced tumors in the zebrafish share many similar features with those of humans. With the recent development in transgenic technology, we are able to control the expression of a specific oncogene in targeted organs for generation of different tissue tumor models in zebrafish. In particular, the fusion of an oncogene and a color reporter, such as the green fluorescent protein, allows us to conveniently monitor transgenic tumors for their initiation, progression, metastasis and transplantation in the transparent zebrafish embryos, as demonstrated in this article with our newly established liver cancer models. What does the future hold in this rapidly growing model organism? Other than understanding the molecular mechanisms of carcinogenesis, one obvious area will be the potential of these models for rapid and high-throughput screening for anticancer drugs.

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

  • Hawkins WE, Overstreet RM, Fournie JW, Walker WW. Development of aquarium fish models for environmental carcinogenesis: tumor induction in seven species. J. Appl. Toxicol.5(4),261–264 (1985).
  • Spitsbergen JM, Kent ML. The state of the art of the zebrafish model for toxicology and toxicologic pathology research--advantages and current limitations. Toxicol. Pathol.31(Suppl.),62–87 (2003).
  • Spitsbergen JM, Tsai HW, Reddy A et al. Neoplasia in zebrafish (Danio rerio) treated with N-methyl-N’-nitro-N-nitrosoguanidine by three exposure routes at different developmental stages. Toxicol. Pathol.28(5),716–725 (2000).▪ A representative study of using a chemical carcinogen to induce zebrafish tumors, which demonstrates the histopathological similarity of fish and human tumors, and thus lays a fundation for the use of zebrafish as a human cancer model.
  • Spitsbergen JM, Tsai HW, Reddy A et al. Neoplasia in zebrafish (Danio rerio) treated with 7,12-dimethylbenz[a]anthracene by two exposure routes at different developmental stages. Toxicol. Pathol.28(5),705–715 (2000).
  • Mizgireuv IV, Majorova IG, Gorodinskaya VM, Khudoley VV, Revskoy SY. Carcinogenic effect of N-nitrosodimethylamine on diploid and triploid zebrafish (Danio rerio). Toxicol. Pathol.32(5),514–518 (2004).
  • Lam SH, Wu YL, Vega VB et al. Conservation of gene expression signatures between zebrafish and human liver tumors and tumor progression. Nat. Biotechnol.24(1),73–75 (2006).
  • Ung CY, Lam SH, Gong Z. Comparative transcriptome analyses revealed conserved biological and transcription factor target modules between the zebrafish and human tumors. Zebrafish6(4),425–431 (2009).
  • Gong ZY, Koh CHV, Nguyen AT et al. The zebrafish model for liver carcinogenesis. In: Molecular Genetics of Liver Neoplasia. Wang X, Grisham J, Thorgeirsson S (Eds). Springer, NY, USA, 197–217 (2010).
  • Jessen JR, Jessen TN, Vogel SS, Lin S. Concurrent expression of recombination activating genes 1 and 2 in zebrafish olfactory sensory neurons. Genesis29(4),156–162 (2001).
  • 10  Langenau DM, Traver D, Ferrando AA et al. Myc-induced T cell leukemia in transgenic zebrafish. Science299(5608),887–890 (2003).▪ First tumor model using transgenic zebrafish. Broadens the choice of animal models in human cancer studies.
  • 11  Yang HW, Kutok JL, Lee NH et al. Targeted expression of human MYCN selectively causes pancreatic neuroendocrine tumors in transgenic zebrafish. Cancer Res.64(20),7256–7262 (2004).
  • 12  Park SW, Davison JM, Rhee J, Hruban RH, Maitra A, Leach SD. Oncogenic KRAS induces progenitor cell expansion and malignant transformation in zebrafish exocrine pancreas. Gastroenterology134(7),2080–2090 (2008).
  • 13  Langenau DM, Keefe MD, Storer NY et al. Effects of RAS on the genesis of embryonal rhabdomyosarcoma. Genes Dev.21(11),1382–1395 (2007).
  • 14  Patton EE, Widlund HR, Kutok JL et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr. Biol.15(3),249–254 (2005).
  • 15  Ceol CJ, Houvras Y, Jane-Valbuena J et al. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature471(7339),513–517 (2011).
  • 16  White RM, Cech J, Ratanasirintrawoot S et al. DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature471(7339),518–522 (2011).
  • 17  Lister JA, Robertson CP, Lepage T, Johnson SL, Raible DW. nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate. Development126(17),3757–3767 (1999).
  • 18  White RM, Sessa A, Burke C et al. Transparent adult zebrafish as a tool for in vivo transplantation analysis. Cell Stem Cell2(2),183–189 (2008).
  • 19  Banerjee D, Harfouche R, Sengupta S. Nanotechnology-mediated targeting of tumor angiogenesis. Vascular Cell3(1),3 (2011).
  • 20  Lawson ND, Weinstein BM. In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev. Biol.248(2),307–318 (2002).
  • 21  Stoletov K, Montel V, Lester RD, Gonias SL, Klemke R. High-resolution imaging of the dynamic tumor cell vascular interface in transparent zebrafish. Proc. Natl Acad. Sci. USA104(44),17406–17411 (2007).
  • 22  Stoletov K, Kato H, Zardouzian E et al. Visualizing extravasation dynamics of metastatic tumor cells. J. Cell Sci.123(Pt 13),2332–2341 (2010).
  • 23  Jin SW, Beis D, Mitchell T, Chen JN, Stainier DY. Cellular and molecular analyses of vascular tube and lumen formation in zebrafish. Development132(23),5199–5209 (2005).
  • 24  Zhao C, Wang X, Zhao Y et al. A novel xenograft model in zebrafish for high-resolution investigating dynamics of neovascularization in tumors. PLoS ONE6(7),E21768 (2011).
  • 25  Zhang S, Cao Z, Tian H et al. SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo.Clin. Cancer Res.17(13),4439–4450 (2011).
  • 26  Villanueva A, Minguez B, Forner A, Reig M, Llovet JM. Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy. Ann. Rev. Med.61,317–328 (2010).
  • 27  Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J. Gastroenterol.14(27),4300–4308 (2008).
  • 28  Lu JW, Hsia Y, Tu HC et al. Liver development and cancer formation in zebrafish. Birth Defects Res. C Embryo Today93(2),157–172 (2011).
  • 29  Vucur M, Roderburg C, Bettermann K et al. Mouse models of hepatocarcinogenesis: what can we learn for the prevention of human hepatocellular carcinoma? Oncotarget1(5),373–378 (2010).
  • 30  Ingham PW. The power of the zebrafish for disease analysis. Hum. Mol. Genet.18(R1),R107–R112 (2009).
  • 31  Kari G, Rodeck U, Dicker AP. Zebrafish: an emerging model system for human disease and drug discovery. Clin. Pharmacol. Ther.82(1),70–80 (2007).
  • 32  Lieschke GJ, Currie PD. Animal models of human disease: zebrafish swim into view. Nat. Rev. Genet.8(5),353–367 (2007).
  • 33  Lam SH, Gong ZY. Fish as a model for human disease. In: Human Genetics (4th Edition). Vogel F, Motulsky AG (Eds). Springer Verlag, Heidelberg, Germany, 827–843 (2010).
  • 34  Feitsma H, Cuppen E. Zebrafish as a cancer model. Mol. Cancer Res.6(5),685–694 (2008).
  • 35  Stoletov K, Klemke R. Catch of the day: zebrafish as a human cancer model. Oncogene27(33),4509–4520 (2008).
  • 36  Sukardi H, Chng HT, Chan EC, Gong Z, Lam SH. Zebrafish for drug toxicity screening: bridging the in vitro cell-based models and in vivo mammalian models. Expert Opin. Drug Metab. Toxicol.7(5),579–589 (2011).
  • 37  Evensen L, Link W, Lorens JB. Imaged-based high-throughput screening for anti-angiogenic drug discovery. Curr. Pharm. Des.16(35),3958–3963 (2010).
  • 38  Rubinstein AL, Tran TC, Sneed B et al. Automated, quantitative screening assay for antiangiogenic compounds using transgenic zebrafish. Cancer Res.67(23),11386–11392 (2007).▪ First automated and quantitative screening assay developed specifically for zebrafish drug screen studies.
  • 39  Chen S, Zhu Y, Xia W, Xia S, Xu X. Automated analysis of zebrafish images for phenotypic changes in drug discovery. J. Neurosci. Methods200(2),229–236 (2011).
  • 40  Nguyen AT, Emelyanov A, Koh CH et al. A high level of liver-specific expression of oncogenic KrasV12 drives robust liver tumorigenesis in transgenic zebrafish. Dis. Models Mech.4(6),801–813 (2011).▪▪ First hepatocellular carcinoma (HCC) model driven by oncogene overexpression in the zebrafish, demonstrating the feasibility of generation of zebrafish HCC by high levels of expression of a single oncogene.
  • 41  Zender L, Spector MS, Xue W et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell125(7),1253–1267 (2006).
  • 42  Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology140(5),1410–1426 (2011).
  • 43  Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat. Rev. Mol. Cell Biol.9(7),517–531 (2008).
  • 44  Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl Acad. Sci. USA89(12),5547–5551 (1992).
  • 45  Urlinger S, Baron U, Thellmann M, Hasan MT, Bujard H, Hillen W. Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc. Natl Acad. Sci. USA97(14),7963–7968 (2000).
  • 46  Emelyanov A, Parinov S. Mifepristone-inducible LexPR system to drive and control gene expression in transgenic zebrafish. Dev. Biol.320(1),113–121 (2008).
  • 47  Li Z, Huang X, Zhan H et al. Inducible and repressable oncogenic-addicted hepatocellular carcinoma in Tet-On xmrk transgenic zebrafish. J. Hepatol.doi:10.1016/j.jhep.2011.07.025 (2011) (Epub ahead of print).▪▪ Inducible HCC model using transgenic zebrafish, demonstrating its potential in studying tumor initiation, progression and regression.
  • 48  Schartl M. Homology of melanoma-inducing loci in the genus Xiphophorus. Genetics126(4),1083–1091 (1990).
  • 49  Nguyen AT, Emelyanov A, Koh CH, Spitsbergen JM, Parinov S, Gong Z. An inducible kras V12 transgenic zebrafish model for liver tumorigenesis and chemical drug screening. Dis. Model Mech.doi:10.1242/dmm.008367 (2011) (Epub ahead of print).
  • 50  Weinstein IB. Cancer. Addiction to oncogenes – the Achilles heal of cancer. Science297(5578),63–64 (2002).
  • 51  Mirbahai L, Williams TD, Zhan H, Gong Z, Chipman JK. Comprehensive profiling of zebrafish hepatic proximal promoter CpG island methylation and its modification during chemical carcinogenesis. BMC Genomics12,3 (2011).
  • 52  Zon LI, Bowman TV. Swimming into the future of drug discovery: in vivo chemical screens in zebrafish. ACS Chem. Biol.5(2),159–161 (2010).
  • 53  North TE, Goessling W, Walkley CR et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature447(7147),1007–1011 (2007).▪ First example of using zebrafish to identify potential drug, which is later used in a clinical trial.
  • 54  Sabaawy HE, Azuma M, Embree LJ, Tsai HJ, Starost MF, Hickstein DD. TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA103(41),15166–15171 (2006).
  • 55  Chen J, Jette C, Kanki JP, Aster JC, Look AT, Griffin JD. NOTCH1-induced T-cell leukemia in transgenic zebrafish. Leukemia21(3),462–471 (2007).
  • 56  Zhuravleva J, Paggetti J, Martin L et al. MOZ/TIF2-induced acute myeloid leukaemia in transgenic fish. Br. J. Haematol.143(3),378–382 (2008).
  • 57  Dovey M, White RM, Zon LI. Oncogenic NRAS cooperates with p53 loss to generate melanoma in zebrafish. Zebrafish6(4),397–404 (2009).
  • 58  Ju B, Spitsbergen J, Eden CJ, Taylor MR, Chen W. Co-activation of hedgehog and AKT pathways promote tumorigenesis in zebrafish. Mol. Cancer8,40 (2009).
  • 59  Chen YH, Wang YH, Yu TH, Wu HJ, Pai CW. Transgenic zebrafish line with over-expression of Hedgehog on the skin: a useful tool to screen Hedgehog-inhibiting compounds. Transgenic Res.18(6),855–864 (2009).
  • 60  Santoriello C, Gennaro E, Anelli V et al. Kita driven expression of oncogenic HRAS leads to early onset and highly penetrant melanoma in zebrafish. PLoS ONE5(12),e15170 (2010).
  • 61  Liu NA, Jiang H, Ben-Shlomo A et al. Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. Proc. Natl Acad. Sci. USA108(20),8414–8419 (2011).
  • 62  Gutierrez A, Grebliunaite R, Feng H et al. Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. J. Exp. Med.208(8),1595–1603 (2011).
  • 63  Korzh V, Korzh S, Pan XF et al. Requirement of vasculogenesis and blood circulation in late stages of liver growth in zebrafish. BMC Dev. Biol.8,84 (2008).