A new concept of tumor promotion by tumor necrosis factor-alpha, and cancer preventive agents (-)-epigallocatechin gallate and green tea--a review.

The study of tumor promotion in rodent carcinogenesis using chemical tumor promoters has revealed various tumor promotion pathways, such as the 12-O-tetradecanoylphorbol-13-acetate (TPA) pathway mediated through activation of protein kinase C, and the okadaic acid pathway mediated through inhibition of protein phosphatases 1 and 2A (PP-1 and PP-2A). We previously demonstrated that application of TPA and okadaic acid induced tumor necrosis factor-alpha (TNF-alpha) gene expression in mouse skin, but that tautomycin, which is an inhibitor of PP-1 and PP-2A and not a tumor promoter on mouse skin, did not. Moreover, we found that TNF-alpha stimulated transformation of BALB/3T3 cells initiated with 3-methylcholanthrene 1,000 times stronger than did TPA (Cancer Res. 53, 1982-1985, 1993). This evidence demonstrates a link between the okadaic acid pathway and the endogenous tumor promotion pathway of TNF-alpha. Recently we presented the first evidence that tumor promotion in TNF-alpha(-/-) mice was significantly depressed compared with TNF-alpha(+/+) mice. Thus, in human carcinogenesis, we think that TNF-alpha and other inflammatory cytokines in preneoplastic lesion stimulate tumor promotion and progression of initiated cells as well as premalignant cells. The first part of this paper reports on this TNF-alpha tumor promotion pathway. In the second part, we report a promising screening method for cancer preventive agents, based on evidence that pretreatment with agents such as tamoxifen, sulindac, 1alpha, 25-(OH)2 vitamin D3, quercetin, caffeic acid phenethyl ester, and (-)-epigallocatechin gallate (EGCG) commonly inhibited TNF-alpha release from BALB/3T3 cells induced by okadaic acid. EGCG, the main constituent of Japanese green tea, and green tea itself are acknowledged cancer preventives in Japan, and this paper presents evidence of their effectiveness in both a high-risk group and the general population.