Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis

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Abstract

Inhibition of telomerase is proposed to limit the growth of cancer cells by triggering telomere shortening and cell death1,2,3,4,5,6,7,8,9. Telomere maintenance by telomerase is sufficient, in some cell types, to allow immortal growth1,2,3,4,5. Telomerase has been shown to cooperate with oncogenes in transforming cultured primary human cells into neoplastic cells, suggesting that telomerase activation contributes to malignant transformation6. Moreover, telomerase inhibition in human tumour cell lines using dominant-negative versions of TERT leads to telomere shortening and cell death7,8. These findings have led to the proposition that telomerase inhibition may result in cessation of tumour growth9. The absence of telomerase from most normal cells supports the potential efficacy of anti-telomerase drugs for tumour therapy, as its inhibition is unlikely to have toxic effects. Mice deficient for Terc RNA (encoding telomerase) lack telomerase activity, and constitute a model for evaluating the role of telomerase and telomeres in tumourigenesis10. Late-generation Terc−/− mice show defects in proliferative tissues10,11,12,13,14,15 and a moderate increase in the incidence of spontaneous tumours in highly proliferative cell types (lymphomas, teratocarcinomas12). The appearance of these tumours is thought to be a consequence of chromosomal instability in these mice10,12,16,17. These observations have challenged the expected effectiveness of anti-telomerase–based cancer therapies18. Different cell types may nonetheless vary in their sensitivity to the chromosomal instability produced by telomere loss or to the activation of telomere-rescue mechanisms. Here we show that late-generation Terc−/− mice, which have short telomeres and are telomerase-deficient10, are resistant to tumour development in multi-stage skin carcinogenesis. Our results predict that an anti-telomerase–based tumour therapy may be effective in epithelial tumours.

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Figure 1: Papillomas in wild-type and Terc−/− mice.
Figure 2: Histopathology of skin lesions.
Figure 3: Telomere fluorescence in skin sections.
Figure 4: p53 and p21 concentrations in wild-type and Terc−/− skin keratinocytes.

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Acknowledgements

We thank E. Santos and J. Martín-Caballero for mouse care and genotyping, and C. Mark and M. Serrano for critical reading of the manuscript. E.G.-S. is a predoctoral fellow from Fondo de Investigaciones Sanitarias (FIS). E.S. is a predoctoral fellow from Regional Government of Madrid (CAM). Research at the laboratory of M.A.B. is funded by grants PM97-0133 from the Ministry of Science and Technology, Spain, 08.1/0030/98 from CAM, and by grants EURATOM/991/0201, FIGH-CT-1999-00002 and FIS5-1999-00055 from the European Union, and by the DIO. The DIO was founded and is supported by the Spanish Research Council (CSIC) and by The Pharmacia Corporation.

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Correspondence to María A. Blasco.

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González-Suárez, E., Samper, E., Flores, J. et al. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet 26, 114–117 (2000) doi:10.1038/79089

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