Essential role of tumor necrosis factor alpha (TNP-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice

To examine the hypothesis that tumor necrosis factor (TNF) alpha is an esse ntial cytokine in carcinogenesis, we conducted two-stage carcinogenesis exp eriments with an initiator, 7,12-dimethylbenz(a)anthracene (DMBA), plus eit her of two tumor promoters, okadaic acid and 12-O-tetradecanoylphorbol-13-a cetate (TPA), on the skin of TNF-alpha-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%, whe reas the percentage of tumor-bearing TNF+/+ mice was 100%. In TNF-/- mice t reated 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 se en 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 re sidual tumor-promoting activity in TNF-/- mice, we also investigated the po ssible significance of interleukin (I,) 1 as an additional cytokine in tumo r promotion. A single application of TPA and okadaic acid increased IL l al pha and IL-l beta gene expression in TNF-/- mice. All of our results demons trate that TNF-alpha is the key cytokine for tumor promotion in mouse skin and, very possibly, for carcinogenesis in humans as well.