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Zebrafish as a Biological System for Identifying and Validating Therapeutic Targets and Compounds

  • Nelson S. YeeEmail author
Chapter

Abstract

Pancreatic cancer is a great oncologic challenge. Significant progress has been made in understanding the molecular genetics for transformation of pancreatic epithelia into pre-malignant neoplasia and eventually invasive carcinoma. In spite of these advances, effective treatment is still lacking, and the prognosis of most patients diagnosed with pancreatic cancer is dismal. Molecularly targeted agents show great potential for improving treatment in pancreatic cancer cells and animal models. However, translation of the preclinical studies into clinically useful drugs with meaningful benefits for the patients remains to be accomplished. Development of zebrafish models and application of innovative techniques will enable drug discovery for pancreatic cancer in a whole organism. The established models including wild-type zebrafish larvae, germ-line mutants, transgenics, and xenografts can be utilized to identify the genetic pathways and their interactions that control exocrine pancreatic development and cancer. Combined application of chemical genetic screens with radiographic imaging, nanoparticulate systems, and bioinformatics in the zebrafish models is expected to facilitate identification of drugs that specifically target the signaling networks in pancreatic cancer stem cells, and validation of candidate therapeutics by real-time monitoring of tumor growth. Ultimately, a systems-biology approach that applies the various techniques to the zebrafish models is predicted to lead to discovery of efficacious and safe drugs toward the goal of targeted and personalized therapy in pancreatic cancer.

Keywords

Pancreatic Cancer Zebrafish Embryo Exocrine Pancreas Acinar Cell Carcinoma Adult Zebrafish 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The work in the author’s laboratory is supported by the National Institutes of Health (DK060529, DK071960); Pilot Grant in Translational Research by the Department of Internal Medicine of the University of Iowa; the American Cancer Society Junior Faculty Seed Grant Award (ACS #IRG-77-004-31); the Fraternal Order of Eagles, and the Cancer Center Support Grant (CA086862) by the National Cancer Institute to the Holden Comprehensive Cancer Center at the University of Iowa. The Zebrafish International Resource Center is supported by a grant (RR12546) from the NIH-NCRR.

References

  1. Amatruda JF, Shepard JL, Stern HM et al (2002) Zebrafish as a cancer model system. Cancer Cell 1:1–4CrossRefGoogle Scholar
  2. Berman DM, Karhadkar SS, Maitra A et al (2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:846–851CrossRefPubMedGoogle Scholar
  3. Bloomston M, Frankel WL, Petrocca F et al (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297:1901–1908CrossRefPubMedGoogle Scholar
  4. Chen W, Burgess S, Hopkins N (2001) Analysis of the zebrafish smoothened mutant reveals conserved and divergent function of hedgehog activity. Development 128:2385–2396PubMedGoogle Scholar
  5. Chen J, Ruan H, Ng SM et al (2005a) Loss of function of def selectively up-regulates D113p53 expression to arrest expansion growth of digestive organs in zebrafish. Genes Dev 19:2900–2911CrossRefGoogle Scholar
  6. Chen PY, Manninga H, Slanchev K et al (2005b) The developmental miRNA profiles of zebrafish as determined by small RNA cloning. Genes Dev 19:1288–1293CrossRefGoogle Scholar
  7. Chen R, Yi EC, Donohoe S et al (2005c) Pancreatic cancer proteome: The proteins that underlie invasion, metastasis, and immunologic escape Gastroenterology 129:1187–1197Google Scholar
  8. Chun SG, Zhou W, Yee NS (2009) Combined targeting of histone deacetylases and hedgehog signaling enhances cytotoxicity in pancreatic cancer. Cancer Biol Ther 8: 1328–1339CrossRefGoogle Scholar
  9. Davuluri G, Gong W, Yusuff S et al (2008) Mutation of the zebrafish nucleoporin elys sensitizes tissue progenitors to replication stress. PLoS Genet 4:1–13CrossRefGoogle Scholar
  10. De La O JP, Emerson LL, Goodman JL et al (2008) Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci USA 105:18907–18912CrossRefGoogle Scholar
  11. Dong PDS, Provost E, Leach SD et al (2008) Graded levels of Ptf1a differentially regulate endocrine and exocrine fates in the developing pancreas. Genes Dev 22:1145–1450Google Scholar
  12. Esni F, Ghosh B, Biankin AV et al (2004) Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development 131:4213–4224CrossRefPubMedGoogle Scholar
  13. Field HA, Dong PDS, Beis D et al (2003) Formation of the digestive system in zebrafish. II. Pancreas morphogenesis. Dev Biol 261:197–208CrossRefPubMedGoogle Scholar
  14. Goessling W, North TE, Zon L (2007) Ultrasound biomicroscopy permits in vivo characterization of zebrafish liver tumors. Nat Methods 4:551–553CrossRefPubMedGoogle Scholar
  15. Haberland M, Montgomery RL, Olson EN (2008) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42CrossRefGoogle Scholar
  16. Haldi M, Ton C, Seng WL et al (2006) Human melanoma cells transplanted into zebrafish proliferate, migrate, produce melanin, form masses and stimulate angiogenesis in zebrafish. Angiogenesis 9:139–151CrossRefPubMedGoogle Scholar
  17. Hamilton F (1822) An account of the fishes found in the River Ganges and its branches. Archibald Constable and Company, Edinburgh and London, pp 1–405Google Scholar
  18. Haramis APG, Hurlstone A, Velden YVD et al (2006) Adenomatous polyposis coli-deficient zebrafish are susceptible to digestive tract neoplasia. EMBO 7:444–449Google Scholar
  19. Hong CC (2009) Large-scale small-molecule screen using zebrafish embryos. Methods Mol Biol 486:43–55CrossRefPubMedGoogle Scholar
  20. Hruban RH, Goggins M, Parsons JL et al (2000) Progression model for pancreatic cancer. Clin Cancer Res 6:2969–2972PubMedGoogle Scholar
  21. Itoh M, Kim C-H, Palardy G et al (2003) Mind Bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev Cell 4:67–82CrossRefPubMedGoogle Scholar
  22. Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249Google Scholar
  23. Johnson SA, Dubeau L, Johnson DL (2008) Enhanced RNA polymerase III-dependent transcription is required for oncogenic transformation. J Biol Chem 283:19184–19191CrossRefPubMedGoogle Scholar
  24. Jones S, Zhang X, Parsons DW et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806CrossRefPubMedGoogle Scholar
  25. Koorstra J-BM, Hustinx SR, Offerhaus GJA et al (2008) Pancreatic carcinogenesis. Pancreatology 8:110–125CrossRefPubMedGoogle Scholar
  26. Lam SH, Mathavan S, Tong Y et al (2008) Zebrafish Whole-Adult-Organism chemogenomics for large-scale predictive and discovery chemical biology. PLoS Genet 4:1–14CrossRefGoogle Scholar
  27. Le X, Langenau DM, Keefe MD et al (2007) Heat shock-inducible Cre/Lox approaches to induce diverse types of tumors and hyperplasia in transgenic zebrafish. Proc Natl Acad Sci USA 104:9410–9415CrossRefPubMedGoogle Scholar
  28. Lee EJ, Gusev Y, Jiang J et al (2007) Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 120:1046–1054CrossRefPubMedGoogle Scholar
  29. Lee LMJ, Seftor EA, Bonde G et al (2005) The fate of human malignant melanoma cells transplanted into zebrafish embryos: Assessment of migration and cell division in the absence of tumor formation. Dev Dyn 233:1560–1570CrossRefPubMedGoogle Scholar
  30. Lin JW, Biankin AV, Horb ME et al (2004) Differential requirement for ptfla in endocrine and exocrine lineages of developing zebrafish pancreas. Dev Biol 270:474–486CrossRefPubMedGoogle Scholar
  31. Lucitt MB, Price TS, Pizarro A et al (2008) Analysis of the zebrafish proteome during embryonic development. Mol Cell Proteomics 7:981–994CrossRefPubMedGoogle Scholar
  32. Marshall L, Kenneth NS, White RJ (2008) Elevated tRNA(iMet) synthesis can drive cell proliferation and oncogenic transformation. Cell 133:78–89CrossRefPubMedGoogle Scholar
  33. Matthews RP, Lorent K, Manoral-Mobias R et al (2009) TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafish s-adenosylhomocysteine hydrolase. Development 136:865–875CrossRefGoogle Scholar
  34. Mayer AN, Fishman MC (2003) nil per os encodes a conserved RNA recognition motif protein required for morphogenesis and cytodifferentiation of digestive organs in zebrafish. Development 130:3917–3928CrossRefPubMedGoogle Scholar
  35. Miyamoto Y, Maitra A, Ghosh B et al (2003) Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3:565–576CrossRefPubMedGoogle Scholar
  36. Mizgireuv IV, Revskoy SY (2006) Transplantable tumor lines generated in clonal zebrafish. Cancer Res 66:3120–3125CrossRefPubMedGoogle Scholar
  37. Morton JP, Mongeau ME, Klimstra DS et al (2007) Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA 104: 5103–3108CrossRefPubMedGoogle Scholar
  38. Murphey RD, Zon LI (2006) Small molecule screening in the zebrafish. Methods 39:255–261CrossRefPubMedGoogle Scholar
  39. Murtaugh LC (2008) The what, where, when and how of Wnt/β-catenin signaling in pancreas development. Organogenesis 4:81–86CrossRefPubMedGoogle Scholar
  40. Nicole S, Ribatti D, Cotelli F et al (2007) Mammalian tumor xenografts induce neovascularization in zebrafish embryos. Cancer Res 67:2927–2931CrossRefGoogle Scholar
  41. Noel ES, Casal-Sneiro A, Busch-Nentwich E et al (2008) Organ-specific requirements for Hdac1 in liver and pancreas formation. Dev Biol 322:237–250Google Scholar
  42. Park SW, Davison JM, Rhee J et al (2008) Oncogenic KRAS induces progenitor cell expansion and malignant transformation in zebrafish exocrine pancreas. Gastroenterology 134:2080–2090CrossRefPubMedGoogle Scholar
  43. Parkin DM, Whelan SL, Ferlay J et al (2002) Cancer incidence in five continents, vol VIII. International Agency for Research on Cancer, Lyon, FranceGoogle Scholar
  44. Patton EE, Widlund HR, Kutok JL et al (2005) BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol 15:249–254CrossRefPubMedGoogle Scholar
  45. Ryu B, Jones J, Blades NJ et al (2002) Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression. Cancer Res 62:819–826PubMedGoogle Scholar
  46. Schauerte HE, van Eeden FJ, Fricke C et al (1998) Sonic hedgehog is not required for the induction of medial floor plate cells in the zebrafish. Development 125:2983–2993PubMedGoogle Scholar
  47. Shen J, Person MD, Zhu J et al (2004) Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry. Cancer Res 64:9018–9026CrossRefPubMedGoogle Scholar
  48. Spitsbergen J (2007) Imaging neoplasia in zebrafish. Nat Methods 4:548–549CrossRefPubMedGoogle Scholar
  49. Stemple DL (2004) Tilling- a high- throughput harvest for functional genomics. Nat Rev Genet 5:1–6CrossRefGoogle Scholar
  50. Stern HM, Murphey RD, Shepard JL et al (2005) Small molecules that delay S phase suppress a zebrafish bmyb mutant. Nat Chem Biol 1:366–370CrossRefPubMedGoogle Scholar
  51. Stoletov K, Montel V, Lester RD et al (2007) High-resolution imaging of the dynamic tumor cell-vascular interface in transparent zebrafish. Proc Natl Acad Sci USA 104:17406–17411CrossRefPubMedGoogle Scholar
  52. Streisinger G, Walker C, Dower N et al (1981) Production of clones of homozygous diploid zebra fish (Brachydanio rerio). Nature 291:293–296CrossRefPubMedGoogle Scholar
  53. Stuckenholz C, Lu L, Thakur P et al (2009) FACs-assisted microarray profiling implicates novel genes and pathways in zebrafish gastrointestinal tract development. Gastroenterology 137:1321–1332Google Scholar
  54. Szafranska AE, Davison TS, John J et al (2007) MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26:4442–4452Google Scholar
  55. Tay TL, Lin Q, Seow TK et al (2006) Proteomic analysis of protein profiles during early development of the zerbafish, Danio rerio. Proteomics 6:3176–3188CrossRefPubMedGoogle Scholar
  56. Thayer SP, Magliano MP, Heiser PW et al (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425:851–856CrossRefPubMedGoogle Scholar
  57. Tiso N, Moro E, Argenton F (2009) Zebrafish pancreas development. Mol Cell Endocrinol 312:24–30Google Scholar
  58. Topczewska K, Postovit LM, Margaryan NV et al (2006) Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nature Med 12: 925–932CrossRefPubMedGoogle Scholar
  59. Varga ZM, Amores A, Lewis KE et al (2001) Zebrafish smoothened functions in ventral neural tube specification and axon tract formation. Development 128:3497–3509PubMedGoogle Scholar
  60. Wan H, Korzh S, Li Z et al (2006) Analyses of pancreas development by generation of gfp transgenic zebrafish using an exocrine pancreas-specific elastaseA gene promoter. Exp Cell Res 312:1526–1539CrossRefPubMedGoogle Scholar
  61. White RJ (2008) RNA polymerases I and III, non-coding RNAs and cancer. Trends Genet 24:622–629CrossRefPubMedGoogle Scholar
  62. White RM, Sessa A, Burke C et al (2008) Transparent adult zebrafish as tool for in vivo transplantation analysis. Cell Stem Cell 2:183–189CrossRefPubMedGoogle Scholar
  63. Yee NS, Pack M (2005) Zebrafish as a model for pancreatic cancer research. Methods Mol Med 103:273–298PubMedGoogle Scholar
  64. Yee NS, Yusuff S, Pack M (2001) Zebrafish pdx1 morphant displays defects in pancreas development and digestive organ chirality, and potential identifies a multipotent pancreas progenitor cell. Genesis 30:137–140CrossRefPubMedGoogle Scholar
  65. Yee NS, Furth EE, Pack M (2003) Clinicopathologic and molecular features of pancreatic adenocarcinoma associated with Peutz-Jeghers Syndrome. Cancer Biol Ther 2:1 38–47Google Scholar
  66. Yee NS, Lorent K, Pack M (2005) Exocrine pancreas development in zebrafish. Dev Biol 284:84–101CrossRefPubMedGoogle Scholar
  67. Yee NS, Gong W, Huang Y et al (2007) Mutation of RNA pol III subunit rpc2/polr3b leads to deficiency of subunit Rpc11 and disrupts zebrafish digestive development. PLoS Biol 5:2484–2492CrossRefGoogle Scholar
  68. Yee NS, Zhou W, Chun SG, Liang I-C (submitted) Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancerGoogle Scholar
  69. Zecchin E, Mavropoulos A, Devos N et al (2004) Evolutionary conserved role of ptfla in the specification of exocrine pancreatic fates. Dev Biol 268:174–184CrossRefPubMedGoogle Scholar
  70. Zon LI, Peterson RT (2005) In vivo drug discovery in the zebrafish. Nature Rev Drug Discov 4:35–44CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Carver College of Medicine, Holden Comprehensive Cancer CenterUniversity of IowaIowa CityUSA

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