The Development and Use of Genetically Tractable Preclinical Mouse Models

  • Michael T. Hemann


Mouse models have made fundamental contributions to our understanding of tumor progression and the basic molecular genetics of cancer. However, these models have only recently been adapted to effectively study the biology of therapeutic response. The emerging use of preclinical mouse models to study cancer therapy has required the development of tractable genetic systems to rapidly generate tumors bearing complex genetic lesions, as well as an improved understanding of how to most appropriately model human cancer treatment in the mouse. In this chapter, I discuss recent approaches to developing preclinical systems that can be used to effectively model human cancer therapy. A particular focus of this discussion is the emerging set of genetic tools that can be used to accurately recapitulate relevant therapeutic settings. Many of these tools have only been developed in the past several years and speak to the enormous potential of mouse models to fundamentally improve current drug development platforms and inform the further development of personalized cancer therapy.


Epidermal Growth Factor Receptor Therapeutic Response Mutant Epidermal Growth Factor Receptor Preclinical Model Recipient Mouse 
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.


  1. Abate-Shen C et al (2003) Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Cancer Res 63:3886–3890PubMedGoogle Scholar
  2. Adams JM et al (1985) The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318:533–538PubMedCrossRefGoogle Scholar
  3. Beckmann N et al (2007) In vivo mouse imaging and spectroscopy in drug discovery. NMR Biomed 20:154–185PubMedCrossRefGoogle Scholar
  4. Bergers G, Hanahan D (2002) Combining antiangiogenic agents with metronomic chemotherapy enhances efficacy against late-stage pancreatic islet carcinomas in mice. Cold Spring Harb Symp Quant Biol 67:293–300PubMedCrossRefGoogle Scholar
  5. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedCrossRefGoogle Scholar
  6. Bergers G et al (1999) Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284:808–812PubMedCrossRefGoogle Scholar
  7. Bergers G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744PubMedCrossRefGoogle Scholar
  8. Besterman JM (1996) Topoisomerase I inhibition by the camptothecin analog Gl147211C. From the laboratory to the clinic. Ann N Y Acad Sci 803:202–209PubMedCrossRefGoogle Scholar
  9. Boehm T et al (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404–407PubMedCrossRefGoogle Scholar
  10. Bouchard L et al (1989) Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell 57:931–936PubMedCrossRefGoogle Scholar
  11. Boxer RB et al (2004) Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation. Cancer Cell 6:577–586PubMedCrossRefGoogle Scholar
  12. Burgess DJ et al (2008) Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc Natl Acad Sci USA 105:9053–9058PubMedCrossRefGoogle Scholar
  13. Chen Z et al (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730PubMedCrossRefGoogle Scholar
  14. Cherney BW et al (1997) Role of the p53 tumor suppressor gene in the tumorigenicity of Burkitt’s lymphoma cells. Cancer Res 57:2508–2515PubMedGoogle Scholar
  15. Chin L et al (1999) Essential role for oncogenic Ras in tumour maintenance. Nature 400:468–472PubMedCrossRefGoogle Scholar
  16. Collier LS et al (2005) Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse. Nature 436:272–276PubMedCrossRefGoogle Scholar
  17. Cook N et al (2008) K-Ras-driven pancreatic cancer mouse model for anticancer inhibitor analyses. Methods Enzymol 439:73–85PubMedCrossRefGoogle Scholar
  18. Degenhardt K, White E (2006) A mouse model system to genetically dissect the molecular mechanisms regulating tumorigenesis. Clin Cancer Res 12:5298–5304PubMedCrossRefGoogle Scholar
  19. Dickins RA et al (2005) Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nat Genet 37:1289–1295PubMedGoogle Scholar
  20. Ding L et al (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075PubMedCrossRefGoogle Scholar
  21. Dupuy AJ et al (2005) Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436:221–226PubMedCrossRefGoogle Scholar
  22. Edwards SL et al (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111–1115PubMedCrossRefGoogle Scholar
  23. Foster BA et al (1997) Characterization of prostatic epithelial cell lines derived from transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Cancer Res 57:3325–3330PubMedGoogle Scholar
  24. Gibbs JB, Oliff A (1997) The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu Rev Pharmacol Toxicol 37:143–166PubMedCrossRefGoogle Scholar
  25. Greenberg NM, DeMayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO, Cunha GR, Donjacour AA, Matusik RJ, Rosen JM (1995) Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 92(8):3439–3443PubMedCrossRefGoogle Scholar
  26. Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115–122PubMedCrossRefGoogle Scholar
  27. Hanahan D, Wagner EF, Palmiter RD (2007) The origins of oncomice: a history of the first transgenic mice genetically engineered to develop cancer. Genes Dev 21:2258–2270PubMedCrossRefGoogle Scholar
  28. He LZ et al (2001) Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 108:1321–1330PubMedGoogle Scholar
  29. Hemann MT et al (2003) An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo. Nat Genet 33:396–400PubMedCrossRefGoogle Scholar
  30. Hemann MT et al (2004) Suppression of tumorigenesis by the p53 target PUMA. Proc Natl Acad Sci USA 101:9333–9338PubMedCrossRefGoogle Scholar
  31. Hingorani SR et al (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4:437–450PubMedCrossRefGoogle Scholar
  32. Holland EC, Varmus HE (1998) Basic fibroblast growth factor induces cell migration and proliferation after glia-specific gene transfer in mice. Proc Natl Acad Sci USA 95:1218–1223PubMedCrossRefGoogle Scholar
  33. Holland EC et al (1998) A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev 12:3675–3685PubMedCrossRefGoogle Scholar
  34. Hu X et al (2005) mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia 7:356–368PubMedCrossRefGoogle Scholar
  35. Jackson EL et al (2001) Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 15:3243–3248PubMedCrossRefGoogle Scholar
  36. Jain M et al (2002) Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297:102–104PubMedCrossRefGoogle Scholar
  37. Jia S et al (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454:776–779PubMedGoogle Scholar
  38. Johnson JI et al (2001a) Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 84:1424–1431PubMedCrossRefGoogle Scholar
  39. Johnson L et al (2001b) Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410:1111–1116PubMedCrossRefGoogle Scholar
  40. Jones S et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806PubMedCrossRefGoogle Scholar
  41. Kasper S, Smith JA Jr (2004) Genetically modified mice and their use in developing therapeutic strategies for prostate cancer. J Urol 172:12–19PubMedCrossRefGoogle Scholar
  42. Kinkade CW et al (2008) Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118:3051–3064PubMedGoogle Scholar
  43. Klein RD (2005) The use of genetically engineered mouse models of prostate cancer for nutrition and cancer chemoprevention research. Mutat Res 576:111–119PubMedCrossRefGoogle Scholar
  44. Klumb CE et al (2003) DNA sequence profile of TP53 gene mutations in childhood B-cell non-Hodgkin’s lymphomas: prognostic implications. Eur J Haematol 71:81–90PubMedCrossRefGoogle Scholar
  45. Kulke MH et al (2002) A phase II study of troglitazone, an activator of the PPARgamma receptor, in patients with chemotherapy-resistant metastatic colorectal cancer. Cancer J 8:395–399PubMedCrossRefGoogle Scholar
  46. Macdonald JS et al (2005) A phase II study of farnesyltransferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. Invest New Drugs 23:485–487PubMedCrossRefGoogle Scholar
  47. Malumbres M et al (2004) Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118:493–504PubMedCrossRefGoogle Scholar
  48. Martins CP, Brown-Swigart L, Evan GI (2006) Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127:1323–1334PubMedCrossRefGoogle Scholar
  49. Olive KP, Tuveson DA (2006) The use of targeted mouse models for preclinical testing of novel cancer therapeutics. Clin Cancer Res 12:5277–5287PubMedCrossRefGoogle Scholar
  50. Pao W et al (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101:13306–13311PubMedCrossRefGoogle Scholar
  51. Pear WS et al (1998) Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 92:3780–3792PubMedGoogle Scholar
  52. Pelengaris S, Khan M, Evan GI (2002) Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109:321–334PubMedCrossRefGoogle Scholar
  53. Politi K et al (2006) Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 20:1496–1510PubMedCrossRefGoogle Scholar
  54. Sarraf P et al (1998) Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med 4:1046–1052PubMedCrossRefGoogle Scholar
  55. Schmitt CA, Lowe SW (2001) Bcl-2 mediates chemoresistance in matched pairs of primary E(mu)-myc lymphomas in vivo. Blood Cells Mol Dis 27:206–216PubMedCrossRefGoogle Scholar
  56. Schmitt CA, Rosenthal CT, Lowe SW (2000) Genetic analysis of chemoresistance in primary murine lymphomas. Nat Med 6:1029–1035PubMedCrossRefGoogle Scholar
  57. Schmitt CA et al (2002) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109:335–346PubMedCrossRefGoogle Scholar
  58. Sharpless NE, Depinho RA (2006) The mighty mouse: genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 5:741–754PubMedCrossRefGoogle Scholar
  59. Tan TT et al (2005) Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7:227–238PubMedCrossRefGoogle Scholar
  60. Traxler P et al (2001) Tyrosine kinase inhibitors: from rational design to clinical trials. Med Res Rev 21:499–512PubMedCrossRefGoogle Scholar
  61. Twombly R (2002) First clinical trials of endostatin yield lukewarm results. J Natl Cancer Inst 94:1520–1521PubMedGoogle Scholar
  62. van Lohuizen M, Breuer M, Berns A (1989) N-myc is frequently activated by proviral insertion in MuLV-induced T cell lymphomas. EMBO J 8:133–136PubMedGoogle Scholar
  63. van Lohuizen M et al (1991) Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 65:737–752PubMedCrossRefGoogle Scholar
  64. Vargo-Gogola T, Rosen JM (2007) Modelling breast cancer: one size does not fit all. Nat Rev Cancer 7:659–672PubMedCrossRefGoogle Scholar
  65. Ventura A et al (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445:661–665PubMedCrossRefGoogle Scholar
  66. Wendel HG et al (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428:332–337PubMedCrossRefGoogle Scholar
  67. Wendel HG et al (2006) Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. Proc Natl Acad Sci USA 103:7444–7449PubMedCrossRefGoogle Scholar
  68. Williams RT, Roussel MF, Sherr CJ (2006) Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. Proc Natl Acad Sci USA 103:6688–6693PubMedCrossRefGoogle Scholar
  69. Xue W et al (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660PubMedCrossRefGoogle Scholar
  70. Yang FC et al (2008) Nf1-dependent tumors require a microenvironment containing Nf1+/−− and c-kit-dependent bone marrow. Cell 135:437–448PubMedCrossRefGoogle Scholar
  71. Zender L et al (2006) Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125:1253–1267PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.The Koch Institute for Integrative Cancer Research at MITCambridgeUSA

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