Tumor promoters: from chemicals to inflammatory proteins

Abstract

Purpose: The classic two-stage chemical carcinogenesis in rodents is not directly linked to multistage carcinogenesis in humans. In light of our findings that tumor necrosis factor-α (TNF-α) is an endogenous tumor promoter and that TNF-α-inducing protein (Tipα) of Helicobacter pylori stimulates progression of cancer and epithelial-mesenchymal transition, we think it is necessary to re-examine the concept of tumor promoter, from chemicals to inflammatory proteins.

Topics and results: This paper begins with "inflammation," discovered by Virchow, studies of Yamagiwa and Tsutsui, and briefly reviews numerous topics, such as (1) the classic concept of tumor promoter, (2) tumor promotion on mouse skin induced by protein kinase C activators and okadaic acid class compounds, (3) organ specificity of tumor promoters, presenting numerous tumor promoters in various organs, (4) unique tumor promotion induced by inhibitors of protein phosphatases 1 and 2A in mouse skin, rat glandular stomach, and rat liver, (5) the significant role of TNF-α in tumor-promoting inflammation, (6) progression induced by Tipα of H. pylori, and (7) enhancement of cancer treatment efficacy with the combination of anticancer drugs and green tea catechins, to inhibit tumor-promoting inflammation.

Conclusion: Human cancer development involves both durable genetic changes caused by carcinogens and proinflammatory cytokines, and simultaneous inflammation in progression induced by proinflammatory cytokines and chemokines.

Fig. 1

Dose-dependent activation of protein kinase C by TPA (open circles), teleocidin (filled circles), and debromoaplysiatoxin (open triangles)

Fig. 2

Time course of c-jun gene expression in primary cultured rat hepatocytes treated with microcystin-LR (open circles), nodularin (filled circles), and TPA (filled triangles). The c-jun gene transcript was analyzed by Northern blotting using a c-jun cDNA probe

Fig. 3

Mechanisms of tumor promotion and progression. TPA, teleocidin, and aplysiatoxin bind to PKC, while okadaic acid, calyculin A, microcystin-LR, and nodularin bind to PP1 and PP2A. Their interactions increase phosphoproteins and then induce upregulated gene expression including ODC and TNF-α genes. TNF-α protein released from the cell stimulates protein kinases and induces TNF-α release, resulting in tumor promotion and progression

Fig. 4

Induction of TNF-α gene expression in Bhas clones transfected with HP-MP1 gene and pcDNA3.1/hygro(+) vector alone. TNF-α mRNA of Bhas clones is expressed as relative fold expression in comparison with that of nontransfected Bhas 42 cells. Bhas 42 cells: v-Ha-ras transfected BALB/3T3 cells, Bhas/mp1: Bhas 42 cells transfected with vector containing HP-MP1 gene, and Bhas/vec: Bhas 42 cells transfected with vector alone