Radiation-induced apoptosis is modulated by the post-irradiation tumor microenvironment

Abstract

The sensitivity of cells to radiation-induced apoptosis is considered to be low in solid tumors. This is thought to arise largely from inherent resistance caused by apoptotic pathway mutations. However, other factors may contribute to apoptotic resistance. Poor vasculature and abnormal tumor metabolism lead to a tumor microenvironment characterized by conditions of hypoxia, low glucose and extracellular acidosis. Hypoxia during irradiation is well known to cause resistance and is a barrier to successful treatment. We hypothesized that post-irradiation microenvironmental conditions can modulate radiation-induced apoptosis and that this may in part contribute to therapeutic resistance. In order to test this, radiation-induced apoptosis was assessed in U937 cells in suspension and in a novel multicellular agarose-diffusion-system. Post-irradiation hypoxia failed to modify the extent of apoptosis in suspension cells, suggesting that post-irradiation hypoxia may be of little consequence to apoptosis induction in this model. In contrast, low glucose post-irradiation significantly inhibited radiation-induced apoptosis. While short (5h) exposure to acidosis also appeared to inhibit radiation-induced apoptosis, the lack of modulation after extended (20h) exposure suggests that acidosis may only delay apoptosis. In the more complex agarose diffusion-limitation model, radiation-induced apoptotic sensitivity was found to be reduced in cells distant from the diffusion edge representing poorly perfused tumor cells in vivo. Overall, the results suggest that the post-irradiation tumor microenvironment may affect radiation-induced apoptosis and thus may influence therapeutic response. Therefore, the post-irradiation tumor microenvironment may be a target for therapeutic intervention.