Ionizing radiation inhibits tumor neovascularization by inducing ineffective angiogenesis

The vascular effects of ionizing radiation were examined in K1735 murine melanoma tumors. Single-fraction and fractionated radiation virtually arrested growth of these tumors for about a week, after which they resumed more rapid growth. Tumor microvessel density (MVD) and blood perfusion was unchanged seven days after radiation but decreased at later time points after irradiation, when they had grown 10-fold or more. Together with the finding of severe tumor hypoxia and VEGF induction in the latter tumors, the evidence pointed to vascular insufficiency and inhibited neovascularization in tumors that had grown substantially after radiation. Endothelial cell (EC) death detected by TUNEL staining only transiently increased the day following radiation, whereas EC proliferation detected by Ki-67 staining was increased in irradiated tumors that had grown substantially. The fact that increased EC proliferative activity produced fewer vessels suggests that angiogenesis is defective or ineffective after radiation. These results complement recent genetic evidence that EC damage from radiation plays a major role in tissue damage and antitumor efficacy to highlight the importance of EC and vasculature in radiation response. Our studies further show that radiation impact on tumor vasculature extends beyond near-term induction of EC death to more prolonged effects on their ability to support angiogenesis.