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

Oncogene. 2004 Mar 11;23(10):1902-10. doi: 10.1038/sj.onc.1207317.


Keratinocyte-derived TNF-alpha acts as an endogenous tumour promoter and can also regulate AP-1 activity in mouse epidermis. To gain further insight into TNF-alpha 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-alpha-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-alpha receptors act independently via different AP-1 complexes to transduce TNF-alpha signals during tumour promotion. In addition, TNFR2 cooperated with TNFR1 to optimise TNFR1-mediated TNF-alpha bioactivity on keratinocytes in vitro. Our data provide further insight into TNF-alpha signalling in malignancy and provide some rationale for the use of TNF-alpha antagonists in the treatment of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Antigens, CD / genetics*
  • Antigens, CD / physiology
  • Cells, Cultured
  • Epidermis / drug effects
  • Epidermis / pathology
  • Gene Expression Regulation / drug effects
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Tumor Necrosis Factor / deficiency
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / physiology
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin / drug effects
  • Skin / pathology
  • Skin Neoplasms / genetics*
  • Tetradecanoylphorbol Acetate / pharmacology


  • Antigens, CD
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tetradecanoylphorbol Acetate