Endothelial perturbations and therapeutic strategies in normal tissue radiation damage

Abstract

Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Radiotherapy side-effects diminish patients' quality of life, yet effective biological interventions for normal tissue damage are lacking. Protecting microvascular endothelial cells from the effects of irradiation is emerging as a targeted damage-reduction strategy. We illustrate the concept of the microvasculature as a mediator of overall normal tissue radiation toxicity through cell death, vascular inflammation (hemodynamic and molecular changes) and a change in functional capacity. Endothelial cell targeted therapies that protect against such endothelial cell perturbations and the development of acute normal tissue damage are mostly under preclinical development. Since acute radiation toxicity is a common clinical problem in cutaneous, gastrointestinal and mucosal tissues, we also focus on damage in these tissues.

Figure 1

Microvasculature as a mediator of (acute) IR damage and as a target for radiation protection. Tissues that are exposed to a high enough dose of IR develop damage and undergo alterations. In the acute setting, IR induces EC loss through apoptosis and other mechanisms. It also affects vascular inflammatory responses in several ways. ECs become activated, expressing cell surface adhesion molecules and enabling neutrophil transendothelial migration. The timing of heightened neutrophil presence may be important for their effect on tissue damage. Additionally, cytokines are secreted and orchestrate further inflammatory responses. There is no clear consensus in the literature on the kind of hemodynamic changes that ensue, although it is known that vascular tone is lost over time. IR exposure also induces senescence which reduces EC proliferative and angiogenic capacity and causes a chronic pro-inflammatory phenotype. However, treating the tissue with a radioprotectant, radiomitigator or therapeutic that counters the microvascular-mediated damage development can result in reduced normal tissue damage.