Vascular-Mediated Mechanisms and SRS/SBRT

Abstract

While tumor vasculature is required for tumor cell proliferation and survival, it also determines the microenvironmental conditions and radiosensitivity of tumor cells. Vascular-mediated mechanisms contribute significantly to the overall tumor response to stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS). Clinical and preclinical studies indicate that high, single, or hypo-fractionated doses of radiation severely damage tumor microvasculature and reduce tumor blood flow and functional vascular volume, while transiently increasing vessel permeability. The microvascular damage becomes more severe and long lasting with increasing dose. High-dose (>8–10 Gy) irradiation preferentially targets endothelial cells lining tumor blood vessels by activating an acid sphingomyelinase (ASMase)-mediated apoptotic pathway. Upon activation, ASMase hydrolyzes sphingomyelin to generate ceramide, an apoptotic messenger. The tumor response at such high doses is predominantly due to secondary cell death caused by severe vascular deterioration. Recent in vivo studies have demonstrated that enhancement of ceramide signaling through biophysical means — ultrasound-stimulated microbubbles — or chemical means – antiangiogenic drugs – may synergistically increase the vascular response to radiation, allowing the use of lower doses to achieve a curative effect.