The importance of bystander effects in radiation therapy in melanoma skin-cancer cells and umbilical-cord stromal stem cells

Purpose: To examine direct and bystander radiation-induced effects in normal umbilical-cord stromal stem cell (HCSSC) lines and in human cancer cells. Materials and methods: The UCSSC lines used in this study were obtained in our laboratory. Two cell lines (UCSSC 35 and UCSSC 37) and two human melanoma skin-cancer cells (A375 and G361) were exposed to ionizing radiation to measure acute radiation-dosage cell-survival curves and radiation-induced bystander cell-death response. Results: Normal cells, although extremely sensitive to ionizing radiation, were resistant to the bystander effect whilst tumor cells were sensitive to irradiated cell-conditioned media, showing a dose–response relationship that became saturated at relatively low doses. We applied a biophysical model to describe bystander cell-death through the binding of a ligand to the cells. This model allowed us to calculate the maximum cell death ( vmax) produced by the bystander effect together with its association constant (KBy) in terms of dose equivalence (Gy). The values obtained for KBy in A375 and G361 cells were 0.23 and 0.29 Gy, respectively. Conclusion: Our findings help to understand how anticancer therapy could have an additional decisive effect in that the response of sub-lethally hit tumor cells to damage might be required for therapy to be successful because the survival of cells communicating with irradiated cells is reduced. 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 102 (2012) 450–458 Variation in the intrinsic radiosensitivity of both human-tumor and normal-tissue cells is already recognized, and these differences may be related to clinical curability and tolerance to treatment [1]. At present, choice of the appropriate dose for all patients is based on a balance between minimizing the incidence of severe normaltissue complications and maximizing the probability of local control. Radiation is an unusual toxic agent in that the timing of tissue damage can vary widely from one patient to the next [2,3]. Radiotherapy is based on traditional radiobiological models, in which the effect of radiation on cells is assumed to result from a cascade of simultaneous or successive events that start with the initial damage to DNA. Radiation-induced lethal or potentially lethal damage to the DNA of cells can be explained by linear-quadratic models, which can also be used to describe the relationship between the total isoeffective dose and dose per fraction in fractionated radiation therapy [4]. Based on these models, successful tumor control requires that all clonogenic cells receive a lethal dose. The initial radiation-induced damage to DNA [5] may be a biological indicator of the quantity of energy transferred to the DNA. Nevertheless, the late effects of radiation have still not been fully explained and thus a more general theory to describe the consequences of radiation therapy appears to be necessary [6]. A key consequence in cells is that direct damage occurs to the DNA within the nucleus, producing a range of lesions, of which DNA double-strand breaks (DSBs) play a vital role in determining whether they survive radiation exposure or not [7]. The presence of DNA damage in cells activates repair mechanisms as well as signal transduction pathways, leading to cell cycle arrest and apoptosis. The tumor suppressor protein p53 plays a key role in whether the cell cycle is arrested or apoptosis ensues after a genotoxic attack. Parp-1 participates in the p53 response following irradiation [8,9], but the cascade of events, including intra- and inter-cellular signaling involving free radicals, reactive oxygen species, cytokines or epigenetic changes, has still to be clarified and the results can vary