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The role of stem cells and cell–cell communication in radiation carcinogenesis: ignored concepts

246 National Food Safety Toxicology Center, Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA

Correspondence: J E Trosko. E-mail: james.trosko@ht.msu.edu

Given the complexity of the carcinogenic process and the relative lack of mechanistic understanding about how ionising radiation at low level exposures affects the multistage, multimechanism processes of carcinogenesis, it is imperative that major concepts and paradigms be re-examined when extrapolating from high level to low level results. Clearly, any health effect directly linked to low level radiation exposure must have molecular/biochemical and biological bases. On the other hand, demonstrating some molecular/biochemical or cellular effect, using surrogate systems for the whole human being, may not have a corresponding health effect. Given the general acceptance of an extrapolated linear no-threshold (LNT) model, our current understanding of the multistage, multimechanism process of carcinogenesis cries out for a resolution of a real problem. How can a low level acute, or even chronic, exposure of ionising radiation bring about all the different mechanisms (mutagenic, cytotoxic and epigenetic) and genotypic/phenotypic changes needed to convert a normal cell in a body to an invasive, malignant cell, given all the protective, repair and suppressive systems known to exist in the human body? Until recently, the prevailing paradigm that ionising radiation brings about cancer via DNA damage and its conversion to gene and chromosomal mutations drove our interpretation of radiation carcinogenesis. Today, our knowledge includes both the fact that epigenetic events play a major role in carcinogenesis and that low level radiation can also induce epigenetic events in and between cells in tissues, and this challenges any simple extrapolation of the LNT model. Although a recent description of the "hallmarks" of the cancer process has helped to focus on how ionising radiation might contribute to the induction of cancers, several other previously ignored hallmarks, namely the stem cells in tissues as targets for carcinogenesis and the role of cell–cell communication processes in modulating the radiation effects on the target cell, must be considered.