| Abstract: |
To examine the hypothesis that tumor necrosis factor (TNF) α is an essential cytokine in carcinogenesis, we conducted two-stage carcinogenesis experiments with an initiator, 7,12-dimethylbenz(α)anthracene (DMBA), plus either of two tumor promoters, okadaic acid and 12-O-tetradecanoylphorbol-13- acetate (TPA), on the skin of TNF-α-deficient (TNF(-/-)) mice. TNF(-/-) mice treated with DMBA plus okadaic acid developed no tumors for up to 19 weeks, and at 20 weeks, the percentage of tumor-bearing TNF(-/-) mice was 10%, whereas the percentage of tumor-bearing TNF(+/+) mice was 100%. In TNF(-/-) mice treated with DMBA plus TPA, tumor onset was delayed 4 weeks, and the time to development of small tumors in 100% of mice was 9 weeks later than that seen in TNF(+/+) CD-1 mice. The average number of tumors in TPA-treated TNF(-/-) mice was 2.8, compared with 11.8 for TNF(+/+) CD-1 mice. To understand the residual tumor-promoting activity in TNF(-/-) mice, we also investigated the possible significance of interleukin (IL) I as an additional cytokine in tumor promotion. A single application of TPA and okadaic acid increased IL-1α and IL-1β gene expression in TNF(-/-) mice. All of our results demonstrate that TNF-α is the key cytokine for tumor promotion in mouse skin and, very possibly, for carcinogenesis in humans as well. |
| Keywords: |
protein analysis; mouse; animals; mice; mice, knockout; cell division; gene expression; skin neoplasms; interleukin 1beta; animal experiment; animal model; transfection; carcinogenesis; skin; mice, inbred strains; cytokine; tumor necrosis factor alpha; tumor necrosis factor-alpha; cell line, transformed; genes, ras; tumor growth; interleukin 1alpha; 3t3 cells; interleukin 1; interleukin-1; phorbol 13 acetate 12 myristate; tetradecanoylphorbol acetate; carcinogens; okadaic acid; human; male; female; priority journal; article; 9,10-dimethyl-1,2-benzanthracene; dimethylbenz[a]anthracene
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