Published in Cancer Detection and Prevention 2000; 24(1):91-99.

A New Concept of Tumor Promotion by Tumor Necrosis Factor-α, and Cancer Preventive Agents (-)-Epigallocatechin Gallate and Green Tea - A Review

Hirota Fujiki, M.D., Masami Suganuma Ph.D., Sachiko Okabe, Elsaburo Sueoka, M.D., Kenji Suga, M.D., Kazue Imai Ph.D. and Kel Nakachi, Ph.D.

Saitama Cancer Center Research Institute, Ina, Kitaadachi-gun, Saitama 362-0806, Japan **Present address: Saga Medical School, 5-1-1 Nabeshima, Saga 849-0937, Japan

Address all correspondence to: Dr. Hirota Fajiki, Saitama Cancer Crater Research Institute, Ina, Kitaadachi-gun, Saitania362-0806, Japan.

ABSTRACT The study of tumor promotion in rodent carcinogenesis using chemical tumor promoters hasrevealed various tumor promotion pathways, such as the 12-O-tetradecanoylphorbol-13-acetate (TPA) pathwaymediated through activation of protein kinase C, and the okadaic acid pathway mediated through inhibition of protein phosphatases 1 and 2A (PP-l and PP-2A). We previously demonstrated that application of TPA and okadaicacid induced tutttor necrosis factor-α (TNF-α) gene expression in mouse skin, but that tautomycin, which is aninhibitor of PP-I and PP-2A and not a tumor protnoter on mouse skin, did not. Moreover, we found that TNF-αstimulated transformation of BALB/3T3 cells initiated with 3-methylcholanthrene 1,000 times stronger than didTPA (Cancer Res. 53, 1982-1985, 1993). ‘This evidence demonstrates a link between the okadaic acid pathway andthe endogenous tumor promotion pathway of TNF-α Recently we presented the first evidence that tumor promotion in TNF-α-/- mice was significantly depressed compared with TNF-α+/+ mice. Thus, in human carcinogenesis,we tltink that TNF-α 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-α tamer protootion pathway. In the second part, we report a promising screening method for cancer preventive agents, based on evidencethat pretreatment with agents such as tamoxifen, sulindac. Ice, 25-(OH)2 vitatnin D3, quercetin, caffeic acidphenethyl ester, and (-)-epigallocatechin gallate (EGCG) commonly inhibited TNF-ce release from BALB/3T3 cellsinduced by okadaic acid. EGCG, the main constituent of Japanese green tea, and green tea itself are acknowledgedcancer preventives in Japan, and this paper presents evidence of their effectiveness in both a high-risk group and thegeneral population.

KEY WORDS: okadaic acid, tautomycin, protein phosphatases 1 and 2A, cancer prevention.