Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis

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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Figure 1: Skin carcinogenesis in wild-type and TNF-α–/– mice.
Figure 2: Molecular and cellular changes in skin of wild-type and TNF-α–/– mice during tumor promotion.

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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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Correspondence to Frances 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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