Host factors in the susceptibility of mice to tumour initiating and promoting agents.
It has been known for a long time that skin tumours can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation stage) followed by repetitive treatment with a noncarcinogenic promoter (promotion stage). In mouse skin, the initiation stage requires only a single application of either a direct-acting carcinogen or a procarcinogen and is essentially an irreversible step, which, as data suggest, 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 tumour promoters are not mutagenic but bring about a number of important epigenetic changes, such as epidermal hyperplasia and an increase in levels of polyamines, prostaglandins and dark basal keratinocytes as well as other embryonic conditions. Recently, tumour promotion in mouse skin was shown to consist of at least two stages, each of which 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 tumour promoters, calcium ionophore A23187, hydrogen peroxide and wounding, is needed; (2) it is partially irreversible; (3) increases in dark basal keratinocytes and prostaglandins are important; and (4) it can be inhibited by anti-inflammatory 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, anti-inflammatory steroids and polyamine synthesis inhibitors. Although skin tumour promotion has been studied extensively in mice, not all strains and stocks of mice are susceptible to phorbol ester tumour promoters. In this regard, C57Bl/6 mice appear to be fairly resistant to these tumour promoters. Not all species are equally susceptible to phorbol ester tumour promotion (mouse greater than rat greater than hamster, and the miniature swine is fairly resistant). It is not presently known if other experimental systems of carcinogenesis or the induction of human cancer go through a series of stages similar to that in the mouse skin.
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000503:physiopathology; D010703:Phorbol Esters / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D012878:Skin Neoplasms / Q000139:chemically induced; D013045:Species Specificity
D002273:Carcinogens; D010703:Phorbol Esters; D010835:Phytohemagglutinins