Following up on cell death due to lethal gene or chromosome mutations, it has to be said that not all agents which cause cell death have to damage DNA or cause mutations. A cell can be killed by many non-specific, ubiquitous means (i.e., membrane disruption causing ionic imbalances) or by very specific means (i.e., inhibition of vital enzymes). While it should be obvious that dead cells do not give rise to cancers, cell death could contribute to the carcinogenic process by inducing surviving stem or progenitor cells to proliferate. (More will be said on this point when the tumor promotion process is discussed.) It should be noted that if cell proliferation is an important step in the carcinogenic process, then one must recognize that in a solid tissue interactions between cells could influence the cytotoxicity of either ionizing radiations (Kavanagh et al., 1988; Kwok and Sutherland, 1991) or chemicals (Tofilon et al., 1984). This then raises the possibility of thresholds for agents affecting the cytotoxicity-related step in carcinogenesis. In any event, when a cell in a tissue dies, depending on the number and kind, stem or progenitor cells, which were quiescent up to this point, are stimulated either by the loss of contact-inhibition (a process whereby two or more contiguous cells prevent each other from dividing) or by some released mitogenic chemicals from the dead cell or by the loss of some negative growth regulator from the dead cell (Trosko et al., 1990c). Genes in these surviving cells are modulated (expressed and/or repressed) to convert this non-dividing cell to one which can divide to replace the dead cells and to repair the tissue (compensatory hyperplasia).
This process of altering gene expression can be triggered by non-cytotoxic means, as well as the cytotoxic one just mentioned. There are many natural and human-made, endogenous and exogenous chemicals which can alter gene expression. This phenomenon is referred to as an epigenetic change. That is, the alteration of the expression of a gene, at the transcriptional, translational or posttranslational levels, is an epigenetic event. The genetic information has not changed as happens in a mutation, but rather that a gene’s information is now either expressed or repressed in a way such that it now influences the cell. Chemicals, such as growth factors, hormones, neurotransmitters or drugs, such as retinol A, and natural or environmental pollutants, such as phorbol esters, polybrominated biphenyls or dieldrin, can alter gene expression without mutating cells or killing them (Trosko and Chang, 1988a; Trosko and Chang, 1989b; Rrosko et al., 1990a). These chemicals are, therefore, referred to as epigenetic agents. There are some interesting features related to how they trigger gene expression. They usually have threshold levels by which cells respond to them, whether they are receptor or non-receptor dependent. In principal, epigenetic events are reversible, whereas mutations, in practical terms of a cell in the body, are not. Obviously, cell death is an irreversible event. However, there are epigenetic events which can be very stable, such as that which occurs during development. As a totipotent stem cell is committed to become a pluripotent stem cell for a given organ, genes needed for the generation of cells and functions of another organ are stably repressed. On another level of biology, agents which act epigenetically can have some irreversible consequences. For example, if chemicals, such as thalidomide or retinoid, are given to a developing embryo at a critical period, irreversible organogenic events happen, leading to teratogenesis. These critical developmental events must occur at the appropriate times. If an epigenetic chemical blocks the event, even though its molecular actions are reversible on the cell level, they are irreversible on the organism level.
To summarize this section, agents, physical and chemical, this can influence the multistage mechanism of carcinogenesis, do so by either mutating cells (gene or chromosomal), killing them or altering gene expression, epigenetically. A mutagen can act by multiple mechanisms, and it can kill cells. It can indirectly act to stimulate altered gene expression in the surviving cells. In other words, a mutagen, depending on the dose or concentration, can have all three actions. Cytotoxicants do not have to be mutagenic; however, by virtue of killing cells, they are automatically indirect stimulators of altered gene expression in the surviving tissue. Lastly, epigenetic agents can alter gene expression without mutating or killing cells. ( Although all chemicals can kill cells at some concentration .)
