Tumor-initiating agents most likely act by interacting with DNA to induce mutations, gene rearrangements, or gene amplification events that produce a genotypically altered cell. What happens next is that the initiated cells undergo a clonal expansion under the influence of promoting agents that act as mitogens for the transformed cell type. As will be discussed later, these promoting actions appear to be mediated
by cell membrane events, although a direct action of promoters on DNA has also been proposed.
It is important to note that multiple clones of cells are likely to be initiated by a DNAdamaging agent in vivo and that, through a rare second event, one or a small number of these clones progresses to malignant cancer. It may be useful to think of the promotion phase as the stage of cell proliferation and clonal expansion induced by mitogenic stimuli and of the progression phase as the gradual evolution
of genotypically and phenotypically altered cells that occurs due to genetic instability of the
progressing cells. This process leads to the development of cell heterogeneity within a tumor, an idea first described by Foulds53 and later expanded by Nowell.54 During the progression phase, which can take many years in humans, individual tumors develop heterogeneity with respect to their invasive and metastatic characteristics, antigentic specificity, state of cellular differentiation, and responsiveness to hormones, drugs, and immune-modulating agents.
Presumably, some powerful selection process goes on to favor the growth of one progressing cell type
over another. This preferential selection may be due to a certain cell type developing a growth
advantage in the host’s tissues over its peers, as proposed by Nowell, or to the host’s immunologic
defense system being able to recognize and destroy some cell types better than others, thus
providing the selection pressure for expansion of one clone over another, or to a combination of
these factors. Experimental evidence supports such a selection of tumor cells growing in vivo.
For example, Trainer and Wheelock55 have shown that during the growth of L5178Y lymphoma
cells in mice, a continual selection of cells with a decreasing ability to be killed by cytolytic T lymphocytes (CTL) ‘‘armed’’ against the tumor occurs, until an ‘‘emergent phenotype’’ appears that is highly resistant to the CTL cells.
