Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis (original) (raw)

Nature Medicine volume 5, pages 828–831 (1999)Cite this article

An Erratum to this article was published on 01 September 1999

Abstract

Given the associations between chronic inflammation and epithelial cancer1,2 we studied susceptibility to skin carcinogenesis3,4 in mice deficient for the pro-inflammatory cytokine TNF-α (refs. 5,6). TNF-α–/– mice were resistant to development of benign and malignant skin tumors, whether induced by initiation with DMBA and promotion with TPA or by repeated dosing with DMBA. TNF-α–/– mice developed 5–10% the number of tumors developed by wild-type mice during initiation/promotion and 25% of those in wild-type mice after repeated carcinogen treatment. TNF-α could influence tumor and stromal cells during tumor development. The early stages of TPA promotion are characterized by keratinocyte hyperproliferation and inflammation. These were diminished in TNF-α–/– mice. TNF-α was extensively induced in the epidermis, but not the dermis, in TPA-treated wild-type skin, indicating that dermal inflammation is controlled by keratinocyte TNF-α production. Deletion of a TNF-α inducible chemokine also conferred some resistance to skin tumor development. TNF-α has little influence on later stages of carcinogenesis, as tumors in wild-type and TNF-α–/– mice had similar rates of malignant progression. These data provide evidence that a pro-inflammatory cytokine is required for de novo carcinogenesis and that TNF-α is important to the early stages of tumor promotion. Strategies that neutralize TNF-α production may be useful in cancer treatment and prevention.

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Acknowledgements

The authors thank M. Coombs, M. Owen and F. Watt for advice; G. Elia for technical assistance with histopathology; and M. Bradburn for the statistical analysis.

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Authors and Affiliations

  1. Biological Therapy Laboratory, Imperial Cancer Research Fund, PO Box 123, London, WC2A 3PX, UK
    Robert J. Moore, Caroline Arnott, Frances Burke, Lynn Turner & Frances Balkwill
  2. Keratinocyte Laboratory, Imperial Cancer Research Fund, PO Box 123, London, WC2A 3PX, UK
    David M. Owens
  3. Department of Histopathology, Division of Investigative Sciences, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London, W12 ONN, UK
    Gordon Stamp
  4. Clare Hall Laboratories, Imperial Cancer Research Fund, South Mimms, EN6 3LD, Hertfordshire, UK
    Nick East & Hazel Holdsworth
  5. Department of Molecular Genetics, Hellenic Pasteur Institute, Athens, 115 21, Greece
    Manolis Pasparakis & George Kollias
  6. Dana-Faber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA
    Barrett Rollins

Authors

  1. Robert J. Moore
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  2. David M. Owens
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  3. Gordon Stamp
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  4. Caroline Arnott
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  5. Frances Burke
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  6. Nick East
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  7. Hazel Holdsworth
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  8. Lynn Turner
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  9. Barrett Rollins
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  10. Manolis Pasparakis
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  11. George Kollias
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  12. Frances Balkwill
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Correspondence toFrances Balkwill.

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Moore, R., Owens, D., Stamp, G. et al. Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis.Nat Med 5, 828–831 (1999). https://doi.org/10.1038/10552

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