Cancer patients often suffer from local
tumor recurrence after
radiation therapy. Some intracellular and extracellular factors, such as activity of
hypoxia-inducible factor 1 (HIF-1), cell cycle status and
oxygen availability, have been suggested to affect DNA damage responses and eventual radioresistant characteristics of
cancer cells. But when, where, and how these factors affect one another and induce cellular radioresistance is largely unknown. Here, we analyzed mechanistic and spatio-temporal relationships among them in highly heterogeneous tumor microenvironments. Experiments in vitro demonstrated that a decrease in the
glucose concentration reduced the transcriptional activity of HIF-1 and expression of a downstream gene for the cell cycle regulator p27(Kip1) even under hypoxic conditions. Then, the proportion of cells in the radioresistant S phase increased, whereas that in the radiosensitive G1 phase decreased, significantly. Immunohistochemical analyses showed that
cancer cells in perinecrotic hypoxic regions, which should be under low-
glucose conditions, expressed little HIF-1α, and therefore, were mainly in S phase and less damaged by
radiation treatment. Continuous administration of
glucagon, which increases the
blood glucose concentration and so improves
glucose availability in perinecrotic hypoxic regions, induced HIF-1α expression and increased radiation-induced DNA damage. Taken all together, these results indicate that
cancer cells in perinecrotic regions, which would be under low-
glucose and hypoxic conditions, obtain radioresistance by decreasing the level of both HIF-1 activity and p27(Kip1) expression, and adjusting their cell cycle to the radioresistant S phase.