Commentary: is the concept of "tumor promotion" a useful paradigm?

Since the demonstration of the multistage nature of carcinogenesis in experimental work on mouse skin carcinogenesis (and subsequently on various other organ systems in other organisms), the concepts of "initiation", "promotion", and "progression" were operationally generated from empiric data. Because these early observations and concepts had no mechanistic explanations, various hypotheses have been generated to explain the unique characteristics of each phase (e.g., initiation, being irreversible, was ascribed as the result of DNA damage leading to mutagenesis; promotion, being interruptible or reversible, was believed to be caused by epigenetic mechanisms; progression, also being irreversible, was believed to be caused by genetic instability that led to mutagenic and epigenetic changes). In addition, many of the molecular, biochemical, and cellular experiments designed to investigate the mechanistic bases of these phases used technologies that did not always lead to unequivocal interpretations, and because "real-life" carcinogenesis does not mimic controlled experimental conditions of the initiation/promotion/progression experiments, many investigators believe that these concepts have lost their usefulness. In this commentary, I explain some of the confusion concerning the concept of promotion and suggest that, by understanding the limitations of many in vitro assays used to characterize mutagens, by integrating other theories of carcinogenesis (i.e., stem cell theory), and by recognizing the role of epigenetic agents, specifically, modulated gap-junctional intercellular communication, the concept of promotion can provide valuable insights into the carcinogenic process. Mol. Carcinog. 30:131--137, 2001. Copyright 2001 Wiley-Liss, Inc.