Does radiation enhance promotion of already-initiated cells in protracted high-LET carcinogenesis via a bystander effect

摘要

The application of the two-stage clonal expansion (TSCE) model to lung cancer mortality of two populations of miners (the Colorado Plateau miners and the Chinese tin miners) after protracted high-LET radiation exposure (alpha particles of radon-progeny decay) results in the conclusion that the carcinogenesis process in protracted exposures is dominated by the promotion of already-initiated cells. This means that the increase in tumor induction is caused mainly by the modification (i.e., increase) of the net cell proliferation of already-initiated cells during the time of exposure. We hypothesize that this phenomenon is caused by a "bystander effect" whereby normal cells being hit by alpha particles send mitogenic signals to surrounding cells. If the signals are received by (unhit but) already-initiated cells, which are less controlled by homeostasis than the normal cell population, the cells respond by increasing their net cell proliferation, thus increasing the probability of the emergence of a fullymalignant cell. Thus, tissue homeostasis (or the lack thereof) plays an important role. Possible modulators at the cellular level include reactive oxygen species (ROS), transforming growth factor-beta (TGF-beta) within the extracellular matrix and the subsequent up and/or down regulation of genes controlling mitogenic factors within the cell. This process of proliferative stimulation causes an "inverse dose-rate effect" which is more appropriately termed as a protraction effect to distinguish it from the dose-rate effects usually attributed to cellular repair and other mechanisms (e.g., a radiosensitive window in the cell cycle).