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-t etradecanoylphorbol-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 demonstra ted that application of TPA and okadaic acid induced tumor necrosis factor- alpha (TNF-alpha) gene expression in mouse skin, bur that tautomycin, which is an inhibitor of PP-I and PP-2A and not a tumor promoter on mouse skin, did not. Moreover, we found that TNF-alpha stimulated transformation of BAL B/3T3 cells initiated with 3-methylcholanthrene 1,000 times stronger than d id TPA (Cancer Res. 53, 1982-1985, 1993). This evidence demonstrates a link between the okadaic acid pathway and the endogenous tumor promotion pathwa y of TNF-alpha. Recently we presented the first evidence that tumor promoti on in TNF-alpha(-/-) mice was significantly depressed compared with TNF-alp ha(+/+) mice. Thus, in human carcinogenesis, we think that TNF-alpha and ot her inflammatory cytokines in preneoplastic lesion stimulate tumor promotio n and progression of initiated cells as well as premalignant cells. The fir st part of this paper reports on this TNF-alpha tumor promotion pathway. In the second part, we report a promising screening method for cancer preve ntive agents, based on evidence that pretreatment with agents such as tamox ifen, sulindac, 1 alpha, 25-(OH)(2) vitamin D-3, quercetin, caffeic acid ph enethyl ester, and (-)-epigallocatechin gallate (EGCG) commonly inhibited T NF-alpha release from BALB/3T3 cells induced by okadaic acid. EGCG, the mai n constituent of Japanese green tea, and green tea itself are acknowledged cancer preventives in Japan, and this paper presents evidence of their effe ctiveness in both a high-risk group and the general population.