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Comparative biology of mouse versus human cells: modelling human cancer in mice

Abstract

Laboratory mice have represented a powerful experimental system for understanding the intricacy of human cancer pathogenesis. Indeed, much of our current conceptualization of how tumorigenesis occurs in humans is strongly influenced by mouse models of cancer development. However, an emerging body of evidence indicates that there are fundamental differences in how the process of tumorigenesis occurs in mice and humans. What are these species-specific differences and how do they affect the use of mice as models of human tumour pathogenesis?

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Figure 1: Age distribution of cancer in mice and humans.
Figure 2: Karyotype of mouse and human tumours.
Figure 3: Escape from culture- and oncogenic RAS-induced senescence.
Figure 4: Structure of oncogenic HRAS.

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References

  1. Van Dyke, T. & Jacks, T. Cancer modeling in the modern era: progress and challenges. Cell 108, 135–144 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Herzig, M. & Christofori, G. Recent advances in cancer research: mouse models of tumorigenesis. Biochim. Biophys. Acta 1602, 97–113 (2002).

    CAS  PubMed  Google Scholar 

  3. Jonkers, J. & Berns, A. Conditional mouse models of sporadic cancer. Nature Rev. Cancer 2, 251–265 (2002).

    Article  CAS  Google Scholar 

  4. Ames, B. N., Saul, R. L., Schwiers, E., Adelman, R. & Cathcart, R. in Molecular Biology of Ageing (eds Sohal, R. S., Birnbam, L. S. & Cutler, R. G.) 137–144 (Raven Press, New York, 1985).

    Google Scholar 

  5. Holliday, R. Neoplastic transformation: the contrasting stability of human and mouse cells. Cancer Surv. 28, 103–115 (1996).

    CAS  PubMed  Google Scholar 

  6. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Ames, B. N., Shigenaga, M. K. & Hagen, T. M. Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl Acad. Sci. USA 90, 7915–7922 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Adelman, R., Saul, R. L. & Ames, B. N. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc. Natl Acad. Sci. USA 85, 2706–2708 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schwartz, A. G. & Moore, C. J. Inverse correlation between species life span and capacity of cultured fibroblasts to bind 7,12-dimethylbenz(a)anthracene to DNA. Exp. Cell Res. 109, 448–450 (1977).

    Article  CAS  PubMed  Google Scholar 

  10. DePinho, R. A. The age of cancer. Nature 408, 248–254 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Atkin, N. B. Lack of reciprocal translocations in carcinomas. Cancer Genet. Cytogenet. 21, 275–278 (1986).

    Article  CAS  PubMed  Google Scholar 

  15. Heyer, J., Yang, K., Lipkin, M., Edelmann, W. & Kucherlapati, R. Mouse models for colorectal cancer. Oncogene 18, 5325–5333 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Newbold, R. F., Overell, R. W. & Connell, J. R. Induction of immortality is an early event in malignant transformation of mammalian cells by carcinogens. Nature 299, 633–635 (1982).

    Article  CAS  PubMed  Google Scholar 

  17. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    Article  CAS  PubMed  Google Scholar 

  18. Shay, J. W., Wright, W. E. & Werbin, H. Defining the molecular mechanisms of human cell immortalization. Biochim. Biophys. Acta 1072, 1–7 (1991).

    CAS  PubMed  Google Scholar 

  19. Harley, C. B. et al. Telomerase, cell immortality, and cancer. Cold Spring Harb. Symp. Quant. Biol. 59, 307–315 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Prowse, K. R. & Greider, C. W. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc. Natl Acad. Sci. USA 92, 4818–4822 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8, 279–282 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Sherr, C. J. The INK4a/ARF network in tumour suppression. Nature Rev. Mol. Cell Biol. 2, 731–737 (2001).

    Article  CAS  Google Scholar 

  24. Parrinello, S. et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nature Cell Biol. 5, 741–747 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Sherr, C. J. & DePinho, R. A. Cellular senescence: mitotic clock or culture shock? Cell 102, 407–410 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Zindy, F. et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 12, 2424–2433 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Harvey, M. et al. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8, 2457–2467 (1993).

    CAS  PubMed  Google Scholar 

  30. Pantoja, C. & Serrano, M. Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras. Oncogene 18, 4974–4982 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Sage, J. et al. Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. Genes Dev. 14, 3037–3050 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Krimpenfort, P., Quon, K. C., Mooi, W. J., Loonstra, A. & Berns, A. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413, 83–86 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Dannenberg, J. H., van Rossum, A., Schuijff, L. & te Riele, H. Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev. 14, 3051–3064 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Peeper, D. S., Dannenberg, J. H., Douma, S., te Riele, H. & Bernards, R. Escape from premature senescence is not sufficient for oncogenic transformation by Ras. Nature Cell Biol. 3, 198–203 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Wei, W., Hemmer, R. M. & Sedivy, J. M. Role of p14ARF in replicative and induced senescence of human fibroblasts. Mol. Cell Biol. 21, 6748–6757 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dickson, M. A. et al. Human keratinocytes that express hTERT and also bypass a p16INK4a-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics. Mol. Cell Biol. 20, 1436–1447 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stampfer, M. R. et al. Expression of the telomerase catalytic subunit, hTERT, induces resistance to transforming growth factor β growth inhibition in p16INK4A(-) human mammary epithelial cells. Proc. Natl Acad. Sci. USA 98, 4498–4503 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Huot, T. J. et al. Biallelic mutations in p16INK4a confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts. Mol Cell Biol 22, 8135–43 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rogan, E. M. et al. Alterations in p53 and p16INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts. Mol. Cell Biol. 15, 4745–4753 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Brown, J. P., Wei, W. & Sedivy, J. M. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277, 831–834 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Rodriguez-Viciana, P. et al. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89, 457–467 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J. & Der, C. J. Increasing complexity of Ras signaling. Oncogene 17, 1395–1413 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Morales, C. P. et al. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nature Genet. 21, 115–118 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Hahn, W. C. et al. Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol. Cell Biol. 22, 2111–2123 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Janssens, V. & Goris, J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem. J. 353, 417–439 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhao, J. J. et al. Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase. Cancer Cell 3, 483–495 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Lazarov, M. et al. CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nature Med. 8, 1105–1114 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Seger, Y. R. et al. Transformation of normal human cells in the absence of telomerase activation. Cancer Cell 2, 401–413 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Oldham, S. M., Clark, G. J., Gangarosa, L. M., Coffey, R. J. Jr. & Der, C. J. Activation of the Raf-1/MAP kinase cascade is not sufficient for Ras transformation of RIE-1 epithelial cells. Proc. Natl Acad. Sci. USA 93, 6924–6928 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hamad, N. M. et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16, 2045–2057 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Robanus-Maandag, E. et al. p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev. 12, 1599–1609 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Giovannini, M. et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 14, 1617–1630 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Zhu, Y., Ghosh, P., Charnay, P., Burns, D. K. & Parada, L. F. Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296, 920–922 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth Nature Med. 7, 1194–1201 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Coussens, L. M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rabbany, S. Y., Heissig, B., Hattori, K. & Rafii, S. Molecular pathways regulating mobilization of marrow-derived stem cells for tissue revascularization. Trends Mol. Med. 9, 109–117 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Pompei, F., Polkanov, M. & Wilson, R. Age distribution of cancer in mice: the incidence turnover at old age. Toxicol. Ind. Health 17, 7–16 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Bayani, J. et al. Parallel analysis of sporadic primary ovarian carcinomas by spectral karyotyping, comparative genomic hybridization, and expression microarrays. Cancer Res. 62, 3466–3476 (2002).

    CAS  PubMed  Google Scholar 

  63. Shibata, H. et al. Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 278, 120–123 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Xu, X. et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nature Genet. 22, 37–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Jonkers, J. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nature Genet. 29, 418–425 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Reilly, K. M., Loisel, D. A., Bronson, R. T., McLaughlin, M. E. & Jacks, T. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nature Genet. 26, 109–113 (2000).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to those colleagues whose work could not be cited due to space restrictions. We thank I. Ben-Porath, T. Ince and A.E. Karnoub for critical reading of the manuscript, and R. Latek for help with protein modelling. A.R. is currently supported by the Department of Defense CDMRP Grant and R.A.W. is supported by the Department of Health and Human Services, NIH/NCI, Research Program Project Grant.

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DATABASES

LocusLink

APC

CDKN2A

MDM2

MYC

PI3K

RB

TERT

Trp53

WAF1

FURTHER INFORMATION

American Cancer Society, Cancer Facts and Figures 2003

Mouse Models of Human Cancers Consortium, National Cancer Institute

Mouse Tumor Biology Database

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Rangarajan, A., Weinberg, R. Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer 3, 952–959 (2003). https://doi.org/10.1038/nrc1235

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