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Cancer Biology and Transgenic Technology in the Mouse

Bridging the Functional Gap

  • Chapter
The Oncogenomics Handbook

Abstract

Cancer research has benefited from the ability to manipulate the mouse genome. Transgenic technology is being used to produce mice with refined genomic mutations that recapitulate cancer development in the human. Transgenic mice have proven valuable in vivo models to address the biological consequences of mutations found in tumors and interactions of two mutations in the same mouse. Carcinogen screening or therapeutic assessment might be enhanced by conducting 2-yr bioassays in the background of a mutant mouse model. The introduction of transgenic methods to limit mutant gene expression to a single tissue or cell type by Tet-inducible or Cre recombinase-Lox P technology permits genetic models of otherwise lethal phenotypes to be developed. Gene traps in embryonic stem (ES) cells are being used to capture genes and conduct initial screens for gene function in “knockout” mice. Gene “knockdowns” in mouse embryos by lentivirus delivery of small interfering RNA (siRNA) constructs are poised to become valuable tools for studying cancer gene function with some additional technology development. Transgenic mice allow a combinatorial approach utilizing genomic information and physical manipulation of selected genes to dissect pathways altered during tumorigenesis. Finally, although transgenic mouse models are invaluable tools for dissecting cancer and related processes, future goals are to develop “humanized” transgenic mouse models that may more accurately respond to and reflect the human condition.

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References

  1. Hirst GL, Balmain A. Forty years of cancer modelling in the mouse. Eur J Cancer 2004; 40:1794–1780.

    Article  CAS  Google Scholar 

  2. Hardouin S, Nagy A. Mouse models for human disease. Clin Genet 2000; 57:237–244.

    Article  PubMed  CAS  Google Scholar 

  3. Sakatani T, Onyango P. Oncogenomics: prospects for the future. Expert Rev Anticancer Ther 2003; 3:891–901.

    Article  PubMed  Google Scholar 

  4. Winter SF, Cooper AB, Greenberg NM. Models of metastatic prostate cancer: a transgenic perspective. Prostate Cancer Prostatic Dis 2003; 6:204–211.

    Article  PubMed  CAS  Google Scholar 

  5. Sandgren EP, Quaife CJ, Paulovich AG, et al. Pancreatic tumor pathogenesis reflects the causative genetic lesion. Proc Natl Acad Sci USA 1991; 88:93–97.

    Article  PubMed  CAS  Google Scholar 

  6. Perkins AS. Functional genomics in the mouse. Funct Integrat Genom 2002; 2:81–91.

    Article  Google Scholar 

  7. Lakso M, Sauer B, Mosinger B Jr, et al. Targeted oncogene activation by site specific recombination in transgenic mice. Proc Natl Acad Sci USA 1992; 89:6232–6236.

    Article  PubMed  CAS  Google Scholar 

  8. Lamartina S, Silvi L, Roscilli G, et al. Construction of an rtTA2S-M2/tTSkid based transcription regulatory switch that displays no basal activity, good inducibility and high responsiveness to doxycycline in mice and non-human primates. Mol Ther 2003; 7:271–276.

    Article  PubMed  CAS  Google Scholar 

  9. Mitsumori K. Evaluation on carcinogenecity of chemicals using transgenic mice. Toxicology 2002; 181–182:241–244.

    Article  PubMed  Google Scholar 

  10. Jackson-Gusby L. Modeling cancer in the mouse. Oncogene 2002; 21:5504–5514.

    Article  CAS  Google Scholar 

  11. Jaenisch J. Germ line integration and Mendelian transmission of the exogenous Moloney leukemia virus. Proc Natl Acad Sci USA 1976; 73:1260–1264.

    Article  PubMed  CAS  Google Scholar 

  12. Gordon J, Ruddle F. Integration and stable germline transmission of genes injected into mouse pronuclei. Science 1981; 214:1244–1246.

    Article  PubMed  CAS  Google Scholar 

  13. Doetschman T, Gregg RG, Maeda N, et al. Targeted correction of a mutant HPRT gene in mouse embryonic stem cells. Nature 1987; 330:576–578.

    Article  PubMed  CAS  Google Scholar 

  14. Evans M, Kaufman M. Establishment in culture of pluripotent cells from mouse embryos. Nature 1981; 292:154–156.

    Article  PubMed  CAS  Google Scholar 

  15. Mintz B, Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 1975; 72:3585–3589.

    Article  PubMed  CAS  Google Scholar 

  16. Palmiter RD, Brinster RL, Hammer HE, et al. Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Biotechnology 1992; 24:429–433.

    PubMed  CAS  Google Scholar 

  17. Miklyaeva EL, Dong W, Bureau A, et al. Late onset Tay-Sachs disease in mice with targeted disruption of the Hexa gene: behavioral changes and pathology of the central nervous system. Brain Res 2004; 1001(1–2): 37–50.

    Article  PubMed  CAS  Google Scholar 

  18. Tybulewicz VL, Tremblay ML, LaMarca ME, et al. Animal model of Gaucher’s disease from targeted disruption of the mouse glucocerebrosidase gene. Nature 1992; 357:407–410.

    Article  PubMed  CAS  Google Scholar 

  19. Haston CK, McKerlie C, Newbigging S, et al. Detection of modifier loci influencing the lung phenotype of cystic fibrosis knockout mice. Mamm Genome 2002; 13:605–613.

    Article  PubMed  CAS  Google Scholar 

  20. Campbell KH, McWhir J, Ritchieet WA, et al. Sheep cloned by nuclear transfer from a cultured cell line. Nature 1996 380:64–66.

    Article  PubMed  CAS  Google Scholar 

  21. Wakayama T. Cloned mice and embryonic stem cell lines generated from adult somatic cells by nuclear transfer. Oncol Res 2003; 13:309–314.

    PubMed  Google Scholar 

  22. Nagy A, Perrimon N, Sandmeyer S, et al. Tailoring the genome: the power of genetic approaches. Nat Genet 2003; 33(Suppl):276–284.

    Article  PubMed  CAS  Google Scholar 

  23. Houdebine L-M. Animal transgensis and cloning. New York: Wiley, 2003:1–217.

    Book  Google Scholar 

  24. Hofker M, van Deursen J. Transgenic mouse: methods and protocols. Totowa, NJ: Humana Press, 2003: 1–374.

    Google Scholar 

  25. Joyner A. Gene targeting: a practical approach. Oxford: IRL Press.

    Google Scholar 

  26. Hurlin PJ, Zhou ZQ, Toyo-oka K, et al. Deletion of Mnt leads to disrupted cell cycle control and tumorigenesis. EMBO J 2003; 22:4584–4596.

    Article  PubMed  CAS  Google Scholar 

  27. Wijnhoven SWP, van Steeg H. Transgenic and lnockout mice for DNA repair functions in carcinogenesis and mutagenesis. Toxicology 2003; 193:171–187.

    Article  PubMed  CAS  Google Scholar 

  28. Bassing CH, Suh H, Ferguson DO. Histone H2AX: dosage dependent suppressor of oncogenic translocction and tumors. Cell 2003; 114:359–370.

    Article  PubMed  CAS  Google Scholar 

  29. Anisimov VN. Aging and cancer in transgenic mice. Front Biosci 2003; 8:s883–902.

    Article  PubMed  CAS  Google Scholar 

  30. Mills AA, Bradley A. From mouse to man: generating megabase chromosome rearrangements. Trends Genet 2001; 17:331–339.

    Article  PubMed  CAS  Google Scholar 

  31. Rudmann DG, Durham SK. Utilization of genetically altered animals in the pharmaceutical industry. Toxicol Pathol 1999; 27:111–114.

    PubMed  CAS  Google Scholar 

  32. Mullins LJ, Wilmut I, Mullins JJ. Nuclear transfer in rodents. J Physiol 2004; 554(Pt 1):4–12.

    Article  PubMed  CAS  Google Scholar 

  33. McEvoy TG, Ashworth CJ, Rooke JA, Sinclair KD. Consequences of manipulating gametes and embryos of ruminant species. Reproduction 2003; 61(Suppl):167–182.

    PubMed  CAS  Google Scholar 

  34. Hochedlinger K, Jaenisch R. Nuclear transplantation: lessons from frogs and mice. Curr Opin Cell Biol 2002; 14:741–748.

    Article  PubMed  CAS  Google Scholar 

  35. Fan J, Watanabe T. Transgenic rabbits as therapeutic protein bioreactors and human disease models. Pharmacol Ther 2003; 99:261–282.

    Article  PubMed  CAS  Google Scholar 

  36. Sauer B. Cre/lox: one more step in taming the genome. Endocrine 2002; 19:221–228.

    Article  PubMed  CAS  Google Scholar 

  37. Bockamp E, Maringer M, Spangenberg C, et al. Of mice and models: improved animal models for biomedical research. Physiol Genom 2002; 11:115–132.

    CAS  Google Scholar 

  38. Gossen M, Bujard H. Studying gene function in eukaryotes by conditional gene inactivation. Annu Rev Genet 2002; 36:153–173.

    Article  PubMed  CAS  Google Scholar 

  39. Schonig K, Bujard H. Generating conditional mouse mutants via tetracycline-controlled gene expression. Totowa, NJ: Humana Press, 2003:69–104.

    Google Scholar 

  40. Baron U, Bujard H. Tet repressor-based system for regulated gene expression in eukaryotic cells: principles and advances. Methods Enzymol 2000; 327:401–421.

    Article  PubMed  CAS  Google Scholar 

  41. Cronin CA, Gluba W, Scrable H et al. The lac operator-repressor system is functional in the mouse. Genes Dev 2001; 15(12):1506–1517.

    Article  PubMed  CAS  Google Scholar 

  42. Gunther EJ, Moody SE, Belka GK, et al. Impact of P53 loss on reversal andrecurrence of conditional Wnt-induced tumorigenesis. Genes Devel 2003; 17:488–501.

    Article  PubMed  CAS  Google Scholar 

  43. Le Y, Sauer B. Conditional gene knockout using Cre recombinase. Totowa, NJ: Humana Press, 2000: 477–485.

    Google Scholar 

  44. Sauer B. Inducible gene targeting in mice using the Cre/lox system. Methods 1998; 14:381–392.

    Article  PubMed  CAS  Google Scholar 

  45. Lewandoski M. Conditional control of gene expression in the mouse. Nature Rev Genet 2001; 2: 743–755.

    Article  CAS  PubMed  Google Scholar 

  46. Shannon KM, Le Beau MM, Largaespada DA, et al. Modeling myeloid leukemia tumor suppressor gene inactivation in the mouse. Semin Cancer Biol 2001; 11:191–200.

    Article  PubMed  CAS  Google Scholar 

  47. Smith AJ, Xian J, Richardson M, et al. Cre-loxP chromosome engineering of a targeted deletion in the mouse corresponding to the 3p21.3 region of homozygous loss in human tumors. Oncogene 2002; 21:4521–4529.

    Article  PubMed  CAS  Google Scholar 

  48. Soukharev S, Miller JL, Sauer B. Segmental genomic replacement in embryonic stem cells by double lox targeting. Nucleic Acids Res 1999; 27:e21.

    Article  PubMed  CAS  Google Scholar 

  49. Adams LD, Choi L, Xian HQ, et al. Double lox targeting for neural cell transgenesis. Mol Brain Res 2003; 110:220–233.

    Article  PubMed  CAS  Google Scholar 

  50. Grippo PJ, Nowlin PS, Cassaday RD, Sandgren EP. Cell-specific transgene expression from a widely transcribed promoter using Cre/lox mice. Genesis 2002; 32:277–286.

    Article  PubMed  CAS  Google Scholar 

  51. Thyagarajan B, Guimaraes MJ, Groth AC, et al. Mammalian genomes contain active recombinase recognition sites. Gene 2000; 244(1–2):47–54.

    Article  PubMed  CAS  Google Scholar 

  52. Schmidt EE, Taylor DS, Prigge JR, et al. Illegitimate Cre-dependent chromosome rearrangements in transgenic mouse spermatids. Proc Natl Acad Sci USA 2000; 97:13,702–13,707.

    Article  PubMed  CAS  Google Scholar 

  53. Takeuchi T, Nomura T, Tsujita M, et al. Flp recombinase transgenic mice of C57Bl/6 strain for conditional gene targeting. Biochem Biophys Res Commun 2002; 293:953–957.

    Article  PubMed  CAS  Google Scholar 

  54. Chen Y, Rice PA. New insights into site specific recombination from FLP recombinase switches. Annu Rev Biophys Biomol Struct 2003; 32:135–159.

    Article  PubMed  CAS  Google Scholar 

  55. Vooijs M, van der Valk M, te Riele H, Berns A. Flp mediated tissue specific inactivation of the retinoblastoma tumor suppressor gene in the mouse. Oncogene 1998; 17:1–12.

    Article  PubMed  CAS  Google Scholar 

  56. MacPherson D, Sage J, Crowley D, et al. Conditional mutation of Rb causes cell cycle defects without apoptosis in the central nervous system. Mol Cell Biol 2003; 23:1044–1053.

    Article  PubMed  CAS  Google Scholar 

  57. Marino S, Vooijs M, van Der Gulden, et al. Induction of medulloblastomas in P53 null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Devel 2000; 14: 994–1004.

    PubMed  CAS  Google Scholar 

  58. Weinberg R. The retinoblastoma protein and cell cycle control. Cell 1995; 81:323–330.

    Article  PubMed  CAS  Google Scholar 

  59. Biondi C, Gartside M, Tonks I, et al. Targeting and conditional inactivation of the murine MEN1 locus using the Cre recombinase: lox P system. Genesis 2002; 32:150–151.

    Article  PubMed  CAS  Google Scholar 

  60. Bertolinin P, Tong W-M, Herrera L, et al. Pancreatic β-cell specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. Cancer Res 2003; 63: 4836–4841.

    Google Scholar 

  61. Crabtree JS, Scacheri PC, Ward JM, et al. Of mice and MEN1: insulinomas in a conditional mouse knockout. Mol Cell Biol 2003; 23:6075–6085.

    Article  PubMed  CAS  Google Scholar 

  62. Langer SJ, Ghafoori AP, Byrd M, Leinwand L. A genetic screen identifies novel non-compatible lox P sites. Nucleic Acids Res 2002; 30:3067–3077.

    Article  PubMed  CAS  Google Scholar 

  63. St-Onge L, Furth PA, Gruss P. Temporal control of Cre recombinase in transgenic mice by a tetracycline responsive promoter. Nucleic Acids Res 1996; 24:3875–3877.

    Article  PubMed  CAS  Google Scholar 

  64. Schonig K, Schwenk F, Rajewsky K, Bujard H. Stringent doxycycline dependent control of Cre recombinase in vivo. Nucleic Acids Res 2002; 30:e134.

    Article  PubMed  Google Scholar 

  65. Baron U, Schnappinger D, Helbl V, et al. Generation of conditional mutants in higher eukaryotes by switching between expression of two genes. Proc Natl Acad Sci USA 1999; 96:1013–1018.

    Article  PubMed  CAS  Google Scholar 

  66. Kamath R, Ahringer J. Genome-wide RNAi screening in Caenorhabditis elegans. Methods 2003; 30: 313–312.

    Article  PubMed  CAS  Google Scholar 

  67. Dykxhoorn DM, Novina CD, Sharp PA, et al. Killing the messenger: short RNAs that silence gene expression. Nat Rev Mol Cell Biol 2003; 4:457–467.

    Article  PubMed  CAS  Google Scholar 

  68. Torgeir H, Amarzguioui M, Wiiger MT, et al. Positional effects of short interfering targeting human coagulation trigger tissue factor. Nucleic Acids Res 2002; 30:1757–1766.

    Article  Google Scholar 

  69. Rubinson DA, Dillon CP, Kwiatkowski AV, et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nature Gene 2003; 33: 396–400.

    Article  CAS  Google Scholar 

  70. Xia H, Mao Q, Paulson HL, et al. siRNA-mediated gene silencing in vitro and in vivo. Nature Biotechnol 2002; 20:1006–1010.

    Article  CAS  Google Scholar 

  71. Sorensen DR, Leirdal M, Sioud M, et al. Gene silencing by systemic delivery of synthetic siRNAs in adult mice. J Mol Biol 2003; 327:761–766.

    Article  PubMed  CAS  Google Scholar 

  72. Tiscornia G, Singer O, Ikawa M, et al. A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci USA 2003; 100:1844–1848.

    Article  PubMed  CAS  Google Scholar 

  73. Carmell MA, Zhang L, Conklin DS, et al. Germline transmission of RNAi in mice. Nature Struct Biol 2003; 10:91–92.

    Article  PubMed  CAS  Google Scholar 

  74. Reich SJ, Fosnot J, Kuroki A, et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol Vision 2003; 9:210–216.

    CAS  Google Scholar 

  75. Matsukura S, et al. Establishment of conditional vectors for hairpin siRNA knockdowns. Nucleic Acids Res 2003; 31:e77.

    Article  PubMed  Google Scholar 

  76. Czauderna F, Santel A, Hinz M, et al. Inducible shRNA expression for application in a prostate cancer model. Nucleic Acids Res 2003; 31:e127.

    Article  PubMed  CAS  Google Scholar 

  77. Hemann MT, Fridman JS, Zilfou JT, et al. An epi-allelic series of P53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo. Nature Genet 2003; 33:396–400.

    Article  PubMed  CAS  Google Scholar 

  78. Hofmann A, Kessler B, Ewerling S, et al. Efficient transgenesis in farm animals by lentiviral vectors. EMBO Rep 2003; 4:1054–1060.

    Article  PubMed  CAS  Google Scholar 

  79. Klatt P, Serrano M. Engineering cancer resistance in mice. Carcinogenesis 2003; 24:817–826.

    Article  PubMed  CAS  Google Scholar 

  80. Moser R, Quesniaux V, Ryffel B, et al. Use of transgenics animals to investigate drug hypersensitivity. Toxicology 2001; 158:75–83.

    Article  PubMed  CAS  Google Scholar 

  81. Pritchard JB, French JE, Davis BJ, et al. The role of mouse models in carcinogen identification. Environ Health Perspect 2003; 111:444–454.

    Article  PubMed  CAS  Google Scholar 

  82. Kerbels RS. What is the optimal rodent model for anti-tumor drug testing? Cancer Metastasis Rev 1998–1999; 17:301–304.

    Article  Google Scholar 

  83. Abuin A, Holt KH, Platt KA, et al. Full-speed mammalian genetics: in vivo target validation in the drug discovery process. Trends Biotechnol 2002; 20:36–42.

    Article  PubMed  CAS  Google Scholar 

  84. Dirac AM, Bernards R. Reversal of senescence in mouse fibroblasts through suppression of p53. J Biol Chem 2003; 278:11,731–11,734.

    Article  PubMed  CAS  Google Scholar 

  85. Rathkolb B, Fuchs E, Kolb HJ, et al. Large scale N-ethyl N-nitrosurea mutagenesis in mice—from phenotypes to genes. Exp Physiol 2000; 85:635–643.

    Article  PubMed  CAS  Google Scholar 

  86. Skarnes WC, Auerbach BA, Joyner AL. A gene trap approach in mouse embryonic stem cells: the Lac Z reported is activated by splicing reflects endogenous gene expression and is mutagenic in mice. Genes Devel 1992; 6: 903–918.

    Article  PubMed  CAS  Google Scholar 

  87. Wiles MV, Vauti F, Otte J, et al. Establishment of a gene trap sequence tag library to generate mutant mice from embryonic stem cells. Nature Genet 2000; 24:13–24.

    Article  PubMed  CAS  Google Scholar 

  88. Demant P. Cancer susceptibility in the mouse:genetics, biology and implications for human cancer. Nature Rev Genet 2003; 4:721–734.

    Article  CAS  PubMed  Google Scholar 

  89. Tu SP, Jiang XH, Lin MC, et al. Suppression of survivin expression inhibits in vivo tumorigenecity and angiogenesis in gastric cancer. Cancer Res 2003; 63:7724–7732.

    PubMed  CAS  Google Scholar 

  90. Jonkers J, Berns A. Conditional mouse models of sporadic cancer. Nature Rev Cancer 2002; 2: 251–265.

    Article  CAS  Google Scholar 

  91. Rangarajan A, Weinberg RA. Comparative biology of mouse versus human cells: modeling human cancer in mice. Nature Rev Cancer 2003; 3:952–959.

    Article  CAS  Google Scholar 

  92. Hasuwa H, Kaseda K, Einarsdottir T, et al. Small interfering RNA and gene silencing in transgenic mice and rats. FEBS Lett 2002; 532:227–230.

    Article  PubMed  CAS  Google Scholar 

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McKinney, C.E., Shashikant, C.S. (2005). Cancer Biology and Transgenic Technology in the Mouse. In: LaRochelle, W.J., Shimkets, R.A. (eds) The Oncogenomics Handbook. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-893-5:303

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  • DOI: https://doi.org/10.1385/1-59259-893-5:303

  • Publisher Name: Humana Press

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