Mice Deficient in Tumor Necrosis Factor-Alpha Are Resistant to Skin Carcinogenesis

Nat Med. 1999 Jul;5(7):828-31. doi: 10.1038/10552.

Abstract

Given the associations between chronic inflammation and epithelial cancer, we studied susceptibility to skin carcinogenesis in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) 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-alpha(-/-) 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-alpha 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-alpha(-/-) mice. TNF-alpha 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-alpha production. Deletion of a TNF-alpha inducible chemokine also conferred some resistance to skin tumor development. TNF-alpha has little influence on later stages of carcinogenesis, as tumors in wild-type and TNF-alpha(-/-) 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-alpha is important to the early stages of tumor promotion. Strategies that neutralize TNF-alpha production may be useful in cancer treatment and prevention.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Animals
  • Crosses, Genetic
  • Female
  • Immunity, Innate / genetics*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Skin / drug effects
  • Skin / pathology
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • Tetradecanoylphorbol Acetate / toxicity
  • Time Factors
  • Tumor Necrosis Factor-alpha / deficiency*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Tumor Necrosis Factor-alpha
  • 9,10-Dimethyl-1,2-benzanthracene
  • Tetradecanoylphorbol Acetate