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Expression of both TNF-α receptor subtypes is essential for optimal skin tumour development

Oncogene volume 23, pages 1902–1910 (2004)Cite this article

Abstract

Keratinocyte-derived TNF-α acts as an endogenous tumour promoter and can also regulate AP-1 activity in mouse epidermis. To gain further insight into TNF-α signalling during skin tumour formation, mice deficient in TNFR1 (TNFR1−/− mice) or TNFR2 (TNFR2−/− mice) were subjected to chemical carcinogenesis. Tumour multiplicity was significantly reduced in TNFR1−/− and TNFR2−/− mice compared to wild-type (wt) mice, suggesting that both receptors have protumour activity. However, TNFR1−/− mice were markedly more resistant to tumour development than TNFR2−/− mice indicating that TNFR1 is the major mediator of TNF-α-induced tumour formation. TNFR1 and TNFR2 were both expressed in wt epidermis during tumour promotion and by primary keratinocytes in vitro. TPA-induced c-Jun expression was transient in TNFR1−/− and TNFR2−/− compared to wt epidermis and this was reflected by reduced induction of the AP-1-responsive genes granulocyte/macrophage-colony stimulating factor, matrix metalloproteinase-9 and matrix metalloproteinase-3. These genes were differentially regulated in TNFR1−/− compared to TNFR2−/− epidermis, suggesting that the TNF-α receptors act independently via different AP-1 complexes to transduce TNF-α signals during tumour promotion. In addition, TNFR2 cooperated with TNFR1 to optimise TNFR1-mediated TNF-α bioactivity on keratinocytes in vitro. Our data provide further insight into TNF-α signalling in malignancy and provide some rationale for the use of TNF-α antagonists in the treatment of cancer.

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Acknowledgements

The authors thank Nick East for technical assistance; Marian Nakada, Fiona Watt, Frances Burke, Caroline Barton and David Owens for helpful comments on the manuscript; Centocor and Cancer Research UK for funding this research.

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Author notes

  1. Caroline H Arnott and Kate A Scott: Both these authors contributed equally to this paper

Authors and Affiliations

  1. Cancer Research UK Translational Oncology Laboratory, Barts & The London, Queen Mary's School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK

    Caroline H Arnott, Kate A Scott, Robert J Moore, Stephen C Robinson, Richard G Thompson & Frances R Balkwill

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  1. Caroline H Arnott
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  2. Kate A Scott
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  3. Robert J Moore
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Correspondence to Kate A Scott.

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Arnott, C., Scott, K., Moore, R. et al. Expression of both TNF-α receptor subtypes is essential for optimal skin tumour development. Oncogene 23, 1902–1910 (2004). https://doi.org/10.1038/sj.onc.1207317

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