In solid tissues, cells are normally contact-inhibited; therefore there is very little cell division. Promotion must involve a mechanism which overcomes contact inhibition. It has been hypothesized that the inhibition of gap junctional intercellular communication might be the unifying cellular mechanism for any and all kinds of tumor promotion. The function of tumor promotion would appear to increase the target size of the cells containing the first genetic hit, assuming that a cell must accrue at least two, possibly more hits (Potter, 1981a; Trosko and Chang, 1980; Trosko and Chang, 1985). If we assume that the probability of activating an oncogene and losing a tumor suppressor gene in a single cell is the product of two rare independent events, then the probability would be the product of those rare probabilities. If a cell with one hit is clonally amplified, then the longer the promotion period, the greater the number of such cells. Now the probability of a second hit would involve the multiplication of the product of the independent probabilities and the number of cells. This has led to the prediction of the “I-P-I”model of carcinogenesis (Potter, 1981a; Potter, 1984). Experimental evidence seems to be consistent with the hypothesis (Hennings et al., 1983; Reddy and Fialkow, 1987; Scherer et al., 1984).
Progression is assumed to involve the irreversible alteration of one of the promoter-dependent initiated cells to become an autonomous malignant cell. Agents which appear to facilitate this transition seem to be mutagenic (Hennings et al., 1983; Jaffe et al., 1987; Reddy and Fialkow, 1987; Taguchi et al., 1984).
Assumptions related to the oncogene/tumor suppressor gene must also be integrated in this analysis. In general, it is assumed that oncogenes need to be present and activated for a cell to become a tumor. Tumor suppressor genes are assumed to be inactivated or lost in order that a cell with an activated oncogene becomes a tumor cell. Because of many observations which suggest that this assumption might be too simple (e.g., two kinds of activated oncogenes can transform some cells without the known loss of any tumor suppressor genes; one activated oncogene can transform some cells without the known loss of any tumor suppressor genes (Land et al., 1983; New bold and Overell, 1983; Spandidos and Wilkie, 1984)), the Yin-Yang model of oncogene/tumor suppressor genes has been hypothesized. The basic element of this hypothesis is that it is not so much a matter of which or how many oncogenes or tumor suppressor genes have been activated or lost in a given cell, but rather what is the net effect in any given type of cell of the two types of genes on regulating contact-inhibition or gap junctional intercellular communication.
Assumptions related to the mechanisms of action of agents which might act as initiators, promoters and Progressors and which might cause activation of oncogenes and de-activation of tumor suppressor genes need to be reviewed. In general mutagens, which act primarily by deleting genes and being clastogenic rather than by being a “point” mutagen (e.g., ionizing radiation) (Morgan et al., 1990), would be expected to be a better agent at de-activating tumor-suppressor genes than as an activator of oncogenes or as a tumor promoter. However, it is not as clear cut as that, since an agent, such as ionizing radiation, can cause chromosome breaks leading to some stable translocations. If by chance the rearrangement of chromosomes placed an un-mutated, but suppressed oncogene, next to a piece of DNA which now stably activated this gene, then ionizing radiation could affect oncogenes, as well as tumor suppressor genes, controlling cell growth. In addition, ionizing radiation, at doses which could kill a significant number of cells in a tissue, could act as an indirect promoter by causing any surviving initiated cell to go into compensatory hyperplasia. It would seem that this would be described as a threshold-like effect of ionizing radiation in tissues. In general, it would seem that ionizing radiation would be better Progressors, than either an initiator or promoter, even though it has the potential to act at all three stages.
Point mutagens can activate oncogenes, cause cell killing at high doses, and inactivate tumor suppressor genes. In effect, they can act as initiators, indirect promoters by causing cell death-induced compensatory hyperplasia, and Progressors. Ultraviolet light might be considered a good example of a skin cancer initiator and indirect promoter (Trosko, 1981). It might be poor Progressors for the reason that little ultraviolet light would not be able to penetrate many cells to induced damage to the DNA. Chemicals also might be effective as initiators and both direct promoters or indirect promoters by their cytotoxic effects, at least in targeted tissues. Many chemical mutagens might not be good Progressors by virtue of the fact that if they need to be metabolized, many initiated cells seem to be resistant to the very chemical that might have initiated it because they no longer have the same drug metabolizing systems (Morgan et al., 1990).
