Overview of tumor promotion in animals (1983)

Our present understanding of two-stage carcinogenesis encompasses almost four decades of research. Evidence for chemical promotion or cocarcinogenesis was first provided by Berenblum, who reported that a regimen of croton oil (weak or noncarcinogenic) applied alternately with small doses of benzo(a)pyrene (BP) to mouse skin induced a larger number of tumors than BP alone. Subsequently, Moltram found that a single subcarcinogenic dose of BP followed by multiple applications of croton oil could induce a large number of skin tumors. These investigations as well as a number of others, such as Boutwell, Van Duuren and Hecker, were responsible in defining many important aspects of the initiation and promotion of two-stage carcinogenesis. The initiation stage in mouse skin requires only a single application of either a direct-acting carcinogen or a procarcinogen and is essentially an irreversible step which as data suggests probably involves a somatic cell mutation. The promotion stage in mouse skin can be accomplished by a wide variety of weak or noncarcinogenic agents and is initially reversible later becoming irreversible. Current information suggests that skin tumor promoters are not mutagenic but bring about a number of important epigenetic changes, such as epidermal hyperplasia, and an increase in polyamines, prostaglandins and dark basal keratinocytes as well as other embryonic conditions. Recently, tumor promotion in mouse skin was shown to consist of at least two stages, in which each stage can be accomplished by either a known promoter or a weak or nonpromoting agent. Some of the important characteristics of the first stage of promotion are: (1) only one application of a first-stage promoter, such as phorbol ester tumor promoters, calcium ionophore A23187, hydrogen peroxide and wounding is needed; (2) the action is partially irreversible; (3) an increase in dark basal keratinocytes and prostaglandins is important; and (4) such an increase can be inhibited by antiinflammatory steroids and protease inhibitors. The second stage of promotion is initially reversible but later becomes irreversible. Polyamines and epidermal cell proliferation are important events in the second stage of promotion. A number of weak or nonpromoting agents, such as mezerein, are effective second-stage promoters which can be counteracted by retinoic acid, antiinflammatory steroids and polyamine synthesis inhibitors. Although skin tumor promotion has been extensively studied in mice, not all strains and stocks of mice are susceptible to phorbol ester tumor promoters. In this regard, the C57BL/6 mice appear to be fairly resistant to phorbol ester tumor promoters. In addition, not all species are equally susceptible to phorbol ester tumor promotion. Recently the generality of the two-stage system of inducing tumors has been shown to exist in a number of experimental carcinogenesis systems, such as the liver, bladder, lung, colon, esophagus, stomach, mammary gland, pancreas and cells in culture. In these systems, a wide variety of promoting agents such as diet, bile acids, hormones, saccharin, tryptophan, phenobarbital, polychlorinated biphenyls, polybrominated biphenyls and butylated hydroxytoluene have been used to accomplish the tumor promotion stage. It is not presently known if other experimental carcinogenesis systems and the induction of human cancer involves a series of stages similar to that in the mouse skin.