The terms tumor promotion, tumor progression, and multistage carcinogenesis are overlapping and somewhat redundant. Some people use these terms interchangeably and some use them to define discreet steps in the carcinogenesis process. Mechanistically, tumor promotion and progression are a continuum, even though they appear to be ‘‘multistage.’’ Promotion involves a clonal expansion (proliferative phase), and progression usually refers to the genetic alteration phase. But as was noted above, the genes involved in these steps are overlapping or similar. Nevertheless, studies of chemical carcinogenesis models have been used to define and discriminate initiation events and promotion or progression events, and these studies have been useful in determining the genetic and biochemical steps
involved in these steps, as well as providing targets for drug therapy and chemoprevention.
The isolation and characterization of tumorpromoting agents have provided the tools to study the mechanisms of tumor promotion in vitro and in vivo. The reader is reminded that these agents are primarily defined by their ability to promote skin carcinogenesis in the mouse skin-painting assay, and the mechanisms by which they do this may or may not be relevant to the mechanism of tumor promotion and
progression during carcinogenesis in other organs in experimental animals or in humans. Nevertheless, the study of these compounds has been extremely useful in determining the biochemical actions of tumor promoters. Of the promoting agents examined, the phorbol esters have been the most widely studied. Still, one must ask: what the ‘‘phorbol esters’’ are in human carcinogenesis. Most likely they are factors
to which we are continually exposed through our diet, cigarette smoke, and other kinds of environmental
agents. This answer leads to a second question: Do all these agents act through the same receptor or, if not, through the same biochemical steps? The answer is not known, but the list of potential promoters in the human environment is so large that it seems unlikely that they would all act by means of the same
proximal (‘‘receptor’’) mechanism. More likely, they act through different steps in a cascade leading
to the same end point—namely, clonal expansion of initiated cells and progressive selection of genetically variant populations of tumor cells.
Tumor-promoting phorbol esters produce a wide variety of biochemical changes in cells. A number of these changes may be related to the ability of these agents to promote the growth of initiated tumor cells in vivo. Many of the cellular changes induced by phorbol esters are reminiscent of characteristics of the transformed phenotype (see Chapter 4). The effects of phorbol esters on cultured cells include (1) induction of ornithine decarboxylase, 50-nucleotidase, ATPase, and plasminogen activator activities; (2)
stimulation of sugar transport, DNA synthesis, and cell proliferation; and (3) alteration of cell morphology with a loss of cell surface fibronectin and the appearance of a diffuse pattern of actincontaining cytoskeletal elements (reviewed in Reference 60). In addition, phorbol esters stimulate anchorage-independent growth of adenovirus- transformed cells61 and inhibit the terminal differentiation of chicken myoblasts62 and chondroblasts,63 murine lipocytes,64 erythroleukemia cells,65 and neuroblastoma cells.66
Tumor-promoting phorbol esters also transform mouse embryo fibroblasts treated with ultraviolet
light67 and enhance the transformation of human lymphocytes by Epstein-Barr virus.68 These cell culture effects are exerted by low concentrations (nonomolar range) of phorbol esters, and there is generally a correlation between the potencies of phorbol esters for the cell culture effects and their potencies as promoters in mouse skin carcinogenesis. Phorbol esters share a number of biological properties
with epidermal growth factor (EGF) and may act by mechanisms similar to EGF. An interesting observation suggests that TPA can induce neoplastic transformation of fibroblasts from humans genetically predisposed to cancer.69 In these experiments, fibroblasts derivedfrom individuals with familial adenomatosis of the colon and rectum were treated with TPA in culture and then injected into athymic mice. Cultures treated with TPA produced tumors in These results indicate that the fibroblasts from
adenomatosis patients exist in an ‘‘initiated’’ state due to the dominant mutation that produces
the disease, and that this dominantly inherited trait can be induced to undergo malignant progression by treatment with promoting agents alone. This observation supports the idea that initiation of cancer is a mutagenic event and has profound implications for human cancer. For example, if the promoting agents present in our environment could be identified and exposure to them eliminated or significantly diminished, could human cancer be prevented? This approach could conceivably be more effective
than eliminating exposure to initiating agents, since exposure to them need be only very short
and is irreversible. Completely preventing exposure to initiating agents over a lifetime is not
practical; however, if the promotion phase takes 15 to 20 years, expanding it to 30 to 40 years would mean that most individuals could have a life expectancy approaching normal before they developed a fatal cancer.
