Advertisement

Clinical and Translational Oncology

, Volume 8, Issue 5, pp 318–329 | Cite as

Mouse models in oncogenesis and cancer therapy

  • María Virtudes Céspedes
  • Isolda Casanova
  • Matilde Parreño
  • Ramón ManguesEmail author
Educational Series

Abstract

Animal models have been critical in the study of the molecular mechanisms of cancer and in the development of new antitumor agents; nevertheless, there is still much room for improvement. The relevance of each particular model depends on how close it replicates the histology, physiological effects, biochemical pathways and metastatic pattern observed in the same human tumor type. Metastases are especially important because they are the main determinants of the clinical course of the disease and patient survival, and are the target of systemic therapy. The generation of clinically relevant models using the mouse requires their humanization, since differences exist in transformation and oncogenesis between human and mouse. Although genetically modified (GM) mice have been instrumental in understanding the molecular mechanisms involved in tumor initiation, they have been less successful in replicating advanced cancer. Moreover, a particular genetic alteration frequently leads to different tumor types in human and mouse and to lower metastastatic rates in GM mice than in humans. These findings question the capacity of current GM mouse carcinoma models to predict clinical response to therapy. On the other hand, orthotopic (ORT) xenografts of human tumors, or tumor cell lines, in nude mice reproduced the histology and metastatic pattern of most human tumors at advanced stage. Usingex vivo genetic manipulation of human tumor cells, ORT models can be used to molecularly dissect the metastatic process and to evaluatein vivo tumor response to therapy, using non-invasive procedures. Nevertheless, this approach is not useful in the study of the initial stages of tumorigenesis or the contribution of the immune system in this process. Despite ORT models are more promising than the most commonly used subcutaneous xenografts in preclinical drug development, their capacity to predict clinical response to antitumor agents remains to be studied. Humanizing mouse models of cancer will most likely require the combined use of currently available methodologies.

Key words

mouse models orthotopic xenografts genetically modified metastasis preclinical antitumor drug evaluation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Van Dyke T, Jacks T. Cancer modelling in the modern era: progress and challenges. Cell. 2002;108:135–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Grever M, Chaner BA. The National Cancer Institute: Cancer drug discovery and development program. In: (DeVita VT, Jr., Hellman S, Rosenberg SA, eds.). Cancer principles & practice of oncology. (5th ed). Philadelphia (PA): Lippincott-Raven; 1997.Google Scholar
  3. 3.
    DeVita Jr VT, Hellman S, Rosenberg SA (eds.). Cancer: Principles and Practice of Oncology. 7th. Ed. Lippincott Williams & Wilkins. 2005; p. 3120.Google Scholar
  4. 4.
    Ruoslahti E. Fibronectin and its integrin receptors in cancer. Adv Cancer Res. 1999;76:1–20.PubMedCrossRefGoogle Scholar
  5. 5.
    Weber GF (ed.): Cancer Therapy: Molecular Targets in Tumor-Host Interactions. Horizon Bioscience. Editor University of Cincinnati Medical Center, Cincinnati, OH, USA. 2005; p. 398.Google Scholar
  6. 6.
    Hanahan, D., Weinberg RA. The hall-marks of cancer. Cell. 2000;100:57–70.PubMedCrossRefGoogle Scholar
  7. 7.
    McClatchey AI. Modeling metastasis in the mouse. Oncogene. 1999;18(38):5334–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Nowell PC. The clonal evolution of tumor cell populations. Science. 1976,194(4260): 23–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Bernards R Weinberg RA. A progression puzzle. Nature. 2002;418:823.PubMedCrossRefGoogle Scholar
  10. 10.
    Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat. Genet. 2003;33(1):49–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Hunter K. Host genetics influence tumour metastasis. Nat Rev Cancer. 2006;6(2):141–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Khanna C, Hunter K. Modeling metastasisin vivo. Carcinogenesis. 2005;26(3):513–23.PubMedCrossRefGoogle Scholar
  13. 13.
    Slack NH, Bross ID. The influence of site of metastasis on tumour growth and response to chemotherapy. Br J Cancer. 1975;32(1):78–86.PubMedGoogle Scholar
  14. 14.
    Fidler IJ. Orthotopic implantation of human colon carcinomas into nude mice provides a valuable model for the biology and therapy of metastasis. Cancer Metastasis Rev. 1991;10(3):229–43.PubMedCrossRefGoogle Scholar
  15. 15.
    González FJ, Kimura S. Understanding the role of xenobiotic-metabolism in chemical carcinogenesis using gene knockout mice. Mutat Res. 2001;477(1–2):79–87.PubMedGoogle Scholar
  16. 16.
    Mouse Genome Sequence Consortium, Initial sequencing and comparative analysis of the mouse genome. Nature. 2002; 420(6915):520–62.CrossRefGoogle Scholar
  17. 17.
    Rangarajan A, Weinberg RA. Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer. 2005;3(12):952–9.CrossRefGoogle Scholar
  18. 18.
    Jacks T. Tumor suppressor gene mutations in mice. Annu Rev Genet. 1996;30: 603–36.PubMedCrossRefGoogle Scholar
  19. 19.
    Wagner KU. Models of breast cancer: quo vadis, animal modeling? Breast Cancer Res 2004;6(1):31–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Cardiff RD. Validity of mouse mammary tumour models for human breast cancer: comparative pathology. Microsc Res Tech. 2001;52(2):224–30.PubMedCrossRefGoogle Scholar
  21. 21.
    Nandi S, Guzmán RC, Yang J. Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis. Proc Natl Acad Sci USA. 1995;92(9):5650–7.CrossRefGoogle Scholar
  22. 22.
    Grisham JW. Interspecies comparison of liver carcinogenesis: implications for cancer risk assessment. Carcinogenesis. 1997; 18(1):59–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Rosol TJ, Tannehill-Gregg SH, LeRoy BE, Mandl S, Contag CH. Animal models of bone metastasis. Cancer. 2003;97(Suppl 3):S748–57.PubMedCrossRefGoogle Scholar
  24. 24.
    Clarke R. Animal models of breast cancer: their diversity and role in biomedical research. Breast Cancer Res Treat. 1996; 39(1):1–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Hoffman R. Green fluorescent protein imaging of tumour growth, metastasis, and angiogenesis in mouse models. Lancet Oncol. 2002;3(9):546–56.PubMedCrossRefGoogle Scholar
  26. 26.
    Hoffman RM. Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. Invest New Drugs. 1999;17(4):343–59.PubMedCrossRefGoogle Scholar
  27. 27.
    Kim JB, O'Hare MJ, Stein R. Models of breast cancer: is merging human and animal models the future? Breast Cancer Res. 2004;6(1):22–30.PubMedCrossRefGoogle Scholar
  28. 28.
    Heijstek MW, Kranenburg O, Borel Rinkes IH. Mouse models of colorectal cancer and liver metastases. Dig Surg. 2005;22(1–2):16–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Balmain A. Cancer as a complex genetic trait: tumor susceptibility in humans and mouse models. Cell. 2002;108:145–52.PubMedCrossRefGoogle Scholar
  30. 30.
    Kamb A. What's wrong with our cancer models? Nat Rev Drug Discov. 2005;4(2): 161–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Staquel MJ, Byar DP, Green SB, Rozencweig M. Clinical predictivity of transplantable tumor systems in the selection of new drugs for solid tumors: rationale for a three-stage strategy. Cancer Treat Rep. 1983;67(9):753–65.Google Scholar
  32. 32.
    Gura T. Systems for identifying new drugs are often faulty. Science. 1997;273: 1041–2.CrossRefGoogle Scholar
  33. 33.
    Venditti JM, Wesley RA, Plowman J. Current NCl preclinical antitumor screeningin vivo: results of tumor panel screening, 1976–1982, and future directions. Adv Pharmacol Chemother. 1984;20:1–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Wilmanns C, Fan D, O'Brian CA, Bucana CD, Fidler IJ. Orthotopic and ectopic organ environments differentially influence the sensitivity of murine colon carcinoma cells to doxoribicin and 5-fluorouracil. Int J Cancer. 1992;52:98–104.PubMedCrossRefGoogle Scholar
  35. 35.
    Wilmanns C, Fan D, O'Brian CA, et al. Modulation of doxorubicin sensitivity and P-glycoprotein expression in human colon carcinoma cells by ectopic and orthotopic environments in nude mice. Int J Oncol. 1993;3:412–22.Google Scholar
  36. 36.
    Dong Z, Radinsky R, Fan D, Tsan R, Bucana CD, Wilmanns C, Fidler IJ. Organspecific modulation of mdr gene expression and drug resistance in murine colon cancer cells. J Natl Cancer Inst. 1994;86: 913–20.PubMedCrossRefGoogle Scholar
  37. 37.
    Pratesi G, Manzotti C, Tortoreto M, Audisio RA, Zunino F Differential efficacy of flavone acetic against liver versus lung metastases in a human tumour xenograft. Br J Cancer. 1991;63(1):71–4.PubMedGoogle Scholar
  38. 38.
    Staroselsky AN, Fan D, O'Brian CA, Bucana CD, Gupta KP, Fidler IJ. Site-dependent differences in response to the UV-2237 murine fibrosarcoma to systemic therapy with adriamycin. Cancer Res. 1990;50:7775–80.PubMedGoogle Scholar
  39. 39.
    Smith KA, Begg AC, Denekamp J. Differences in chemosensitivity between subcutaneous and pulmonary tumours. Eur J Cancer Clin Oncol. 1985;21(2):249–56.PubMedCrossRefGoogle Scholar
  40. 40.
    Sikder H, Huso DL, Zhang H, et al. Disruption of Id1 reveals major differences in angiogenesis between transplanted and autochthonous tumors. Cancer Cell. 2003;4(4):291–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Alani RM, Silverthorn CF, Orosz K. Tumor angiogensis in mice and men. Cancer Biol Ther. 2004;5(6):498–500.Google Scholar
  42. 42.
    Johnson JI, Decker S, Zaharevitz D, et al. Relationships between drug activity in NCl prelinicalin vitro andin vivo models and early clinical trials. Br J Cancer 2001;84(10):1424–51.PubMedCrossRefGoogle Scholar
  43. 43.
    Farre L, Casanova I, Guerrero S, Trias M, Capella G, Mangues R. Heterotopic implantation alters the regulation of apoptosis and the cell cycle and generates a new metastatic site in a human pancreatic tumor xenograft model. FASEB J. 2002;16 (9):975–82.PubMedCrossRefGoogle Scholar
  44. 44.
    Rosenberg MP, Bortner D. Why transgenic and knockout animal models should be used (for drug efficacy studies in cancer). Cancer Metastasis Rev. 1998–99;17 (5):295–9.CrossRefGoogle Scholar
  45. 45.
    Hahn WC, Weinberg RA. Modelling the molecular circuitry of cancer. Nat Rev Cacer. 2002;2(5):331–41.CrossRefGoogle Scholar
  46. 46.
    Clarke AR. Manipulating the germline: its impact on the study of carcinogenesis Carcinogenesis. 2000;21:435–41.PubMedCrossRefGoogle Scholar
  47. 47.
    Alexander J. Use of transgenic mice in identifying chemopreventive agents. Toxicol Lett. 2000;112–113:507–12.PubMedCrossRefGoogle Scholar
  48. 48.
    Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002;108:155–64.CrossRefGoogle Scholar
  49. 49.
    Berns A. Cancer. Improved mouse models. Nature. 2001;410:1045–4.CrossRefGoogle Scholar
  50. 50.
    Adams JM, Cory S. Transgenic models of tumor development. Science. 1991;254: 1161–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Clarke AR. Manipulating the germline: its impact on the study of carcinogenesis. Carcinogenesis. 2000;21:435–41.PubMedCrossRefGoogle Scholar
  52. 52.
    Hakem Rr, Mak TW. Animal models of tumor suppressor genes. Ann Rev Genet. 2001;35:209–41.PubMedCrossRefGoogle Scholar
  53. 53.
    Tuveson DA, Jacks T. Technologically advanced cancer modeling in mice. Curr Opin Genet Dev. 2002;12(1):105–10.PubMedCrossRefGoogle Scholar
  54. 54.
    Jonkers J, Berns A. Conditional mouse models of sporadic cancer. Nat Rev Cancer. 2002;2:251–65.PubMedCrossRefGoogle Scholar
  55. 55.
    Herzig M, Christofori G. Recent advances in cancer research: mouse models of tumor igenesis. Biochim Biophys Acta. 2002;1602(2):97–113.PubMedGoogle Scholar
  56. 56.
    Gu H, Marth JD, Orban PC, Mossmann H, Rajewsky K. Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science. 1994;265:103–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Lewandoski M. Conditional control of gene expression in the mouse. Nat Rev Genet. 2002;2:743–55.CrossRefGoogle Scholar
  58. 58.
    Su LK, Kinzler KW, Vogelstein B, et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science. 1992;256(5057):668–70.PubMedCrossRefGoogle Scholar
  59. 59.
    Shibata H, Toyama K, Shioya H, et al. Rapid colorectal adenoma formation initiated by conditional, targeting of the Apc gene. Science. 1997;278(5335):120–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med. 2005;11(1):63–70.PubMedCrossRefGoogle Scholar
  61. 61.
    Aguirre AJ, Bardeesy N, Sinha M, López L, Tuveson DA, Horner J, Redston MS, DePinho RA. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 2003;17(24):3112–26.PubMedCrossRefGoogle Scholar
  62. 62.
    Rudolph KL, Millard M, Bosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet. 2001;28(2):155–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Druker BJ. Imatinib as a paradigm of targeted therapies. Adv Cancer Res. 2004;91: 1–30.PubMedCrossRefGoogle Scholar
  64. 64.
    Griffin JD. FLT3 tyrosine kinase as a target in acute leukemias. Hematol J. 2004;5 Suppl 3:S188–90.CrossRefGoogle Scholar
  65. 65.
    Weisberg E, Griffin JD. Resistance to imatinib (Glivec): update on clinical mechanisms. Drug Resist Updat. 2003;6(5):231–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Knudson AG Jr. Overview: genes that predispose to cancer. Mutat Res. 1991;247 (2):185–90.PubMedGoogle Scholar
  67. 67.
    Bankert RB, Egilmez NK, Hess SD. Human-SCID mouse chimeric models for the evaluation of anti-cancer therapies. Trends Immunol. 2001;22(7):386–93.PubMedCrossRefGoogle Scholar
  68. 68.
    De Wever O, Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol. 2003; 200(4):429–47.PubMedCrossRefGoogle Scholar
  69. 69.
    Eccles SA, Fox G, Court W, Sandle J, Dean CJ. Preclinical models for the evaluation of targeted therapies of metastatic disease. Cell Biophys. 1994;24:279–91.PubMedGoogle Scholar
  70. 70.
    Hoffman RM. Orthotopic is orthodox: why are orthotopic-transplant metastatic models different from all other models? J Cell Biochem. 1994;56(1):1–3.PubMedCrossRefGoogle Scholar
  71. 71.
    Killion JJ, Radinsky R, Fidler IJ. Orthotopic models are necessary to predict therapy of transplantable tumors in mice. Cancer Metastasis Rev. 1998–99;17(3):279–84.CrossRefGoogle Scholar
  72. 72.
    Bibby MC. Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages. Eur J Cancer. 2004;40(6):852–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Radinsky R. Modulation of tumor cell gene expression and phenotype by the organ-specific metastatic environment. Cancer Metastasis Rev. 1995;14(4):523–58.CrossRefGoogle Scholar
  74. 74.
    Pocard M, Tsukui H, Salmon RJ, Dutrillaux B, Poupon MF. Efficiency of orthotopic xenograft models for human colon cancers. In Vivo. 1996;10(5):463–9.PubMedGoogle Scholar

Copyright information

© FESEO 2006

Authors and Affiliations

  • María Virtudes Céspedes
    • 1
  • Isolda Casanova
    • 1
  • Matilde Parreño
    • 1
  • Ramón Mangues
    • 1
    Email author
  1. 1.Laboratori d'Investigació GastrointestinalHospital de la Santa Creu i Sant PauBarcelonaSpain

Personalised recommendations