In the eighteenth century, London physician Percival Pott made the first link between cancer and environmental agents when he noted a high incidence of scrotal cancer among chimney sweeps. He hypothesized that it was caused by exposure to coals and tars. Out of this observation grew the two-stage model of cancer development by 1) initiators and 2) promoters. In the years since Pott’s observations a wide range of chemicals, radiation sources, viruses and bacteria have been implicated in the development of cancer. (1)
The initial experimental studies of carcinogenesis were conducted in animals. Chemicals able to react with DNA and non-reactive compounds were both tested for their ability to cause cancer. The model used was mouse skin carcinogenesis. In this system researchers painted test chemicals on the skin and observed the growth of tumors. Researchers found that application of a DNA reactive substance only resulted in tumor formation when the animals were further treated with another non-reactive substance. A compound that reacts with DNA and somehow changes the genetic makeup of the cell is called amutagen. The mutagens that predispose cells to develop tumors are called initiators and the non-reactive compounds that stimulate tumor development are called promoters. Approximately 70% of known mutagens are also carcinogens–cancer-causing compounds. (2) A compound that acts as both an initiator and a promoter is referred to as a ‘complete carcinogen’ because tumor development can occur without the application of another compound. (3)
Initiation is the first step in the two-stage model of cancer development. Initiators, if not already reactive with DNA, are altered (frequently they are made electrophilic) via drug-metabolizing enzymes in the body and are then able to cause changes in DNA (mutations). (3) Since many initiators must be metabolized before becoming active, initiators are often specific to particular tissue types or species. (4) The effects of initiators are irreversible; once a particular cell has been affected by an initiator it is susceptible to promotion until its death. Since initiation is the result of permanent genetic change, any daughter cells produced from the division of the mutated cell will also carry the mutation. (3) In studies of mouse skin carcinogenesis, a linear relationship has been observed between the dose of initiator and the quantity of tumors that can be produced, thus any exposure to the initiator increases risk and this risk increases indefinitely with higher levels of exposure. (4)
Once a cell has been mutated by an initiator, it is susceptible to the effects of promoters. These compounds promote theproliferation of the cell, giving rise to a large number of daughter cells containing the mutation created by the initiator. (2)Promoters have no effect when the organism in question has not been previously treated with an initiator. (4)
Unlike initiators, promoters do not covalently bind to DNA or macromolecules within the cell. Many bind to receptors on the cell surface in order to affect intracellular pathways that lead to increased cell proliferation. (3) There are two general categories of promoters: specific promoters that interact with receptors on or in target cells of defined tissues and nonspecific promoters that alter gene expression without the presence of a known receptor. Promoters are often specific for a particular tissue or species due to their interaction with receptors that are present in different amounts in different tissue types.
While the risk of tumor growth with promoter application is dose-dependent, there is both a threshold and a maximum effect of promoters. Very low doses of promoters will not lead to tumor development and extremely high doses will not produce more risk than moderate levels of exposure. (4)
In mice, repeated promoter applications on initiator-exposed skin produces benign papillomas. Most of these papillomas regress after treatment is stopped, but some progress to cancer. The frequency of progression suggests that the papillomas that progress to cancer have acquired an additional, spontaneous, mutation. (5) The term progression, coined by Leslie Foulds, refers to the stepwise transformation of a benign tumor to a neoplasm and to malignancy. Progression is associated with a karyotypic change since virtually all tumors that advance are aneuploid (have the wrong number of chromosomes). This karyotypic change is coupled with an increased growth rate, invasiveness, metastasis and an alteration in biochemistry and morphology. (4)