Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice.
To examine the hypothesis that tumor necrosis factor (TNF) alpha 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-tetradecanoylphorbol-13-acetate (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%, 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-1alpha and IL-1beta gene expression in TNF-/- mice. All of our results demonstrate that TNF-alpha is the key cytokine for tumor promotion in mouse skin and, very possibly, for carcinogenesis in humans as well.
Suganuma
M
M
Saitama Cancer Center Research Institute, Japan.
Okabe
S
S
Marino
M W
MW
Sakai
A
A
Sueoka
E
E
Fujiki
H
H
D016475:3T3 Cells; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D005260:Female; D011905:Genes, ras; D007375:Interleukin-1 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D019319:Okadaic Acid / Q000633:toxicity; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D002273:Carcinogens; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D019319:Okadaic Acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate