Essential Role of Tumor Necrosis Factor

To examine the hypothesis that tumor necrosis factor (TNF) a is an essential cytokine in carcinogenesis, we conducted two-stage carcinogenesis experiments with an initiator, 7,12-dimethylbenz(a)anthracene (DMBA), plus either of two tumor promoters, okadaic acid and 12-O-tetradecanoylphorbol13-acetate (TPA), on the skin of TNF-a-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) 1 as an additional cytokine in tumor promotion. A single application of TPA and okadaic acid increased IL-1a and IL-1b gene expression in TNF mice. All of our results demonstrate that TNF-a is the key cytokine for tumor promotion in mouse skin and, very possibly, for carcinogenesis in humans as well.