Establishing the Impact of Vascular Damage on Tumor Response to High-Dose Radiation Therapy

Approximately half of all patients with cancer receive radiotherapy, which is conventionally delivered in relatively small doses (1.8-2 Gy) per daily fraction over one to two months. Stereotactic body radiation therapy (SBRT), in which a high daily radiation dose is delivered in 1 to 5 fractions, has improved local control rates for several cancers. However, despite the widespread adoption of SBRT in the clinic, controversy surrounds the mechanism by which SBRT enhances local control. Some studies suggest that high doses of radiation (≥10 Gy) trigger tumor endothelial cell death, resulting in indirect killing of tumor cells through nutrient depletion. On the other hand, mathematical models predict that the high radiation dose per fraction used in SBRT increases direct tumor cell killing, suggesting that disruption of the tumor vasculature is not a critical mediator of tumor cure. Here, we review the application of genetically engineered mouse models to radiosensitize tumor cells or endothelial cells to dissect the role of these cellular targets in mediating the response of primary tumors to high-dose radiotherapy in vivo These studies demonstrate a role for endothelial cell death in mediating tumor growth delay, but not local control following SBRT.