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.

Report of the AAPM TG‐256 on the relative biological effectiveness of proton beams in radiation therapy

“…For tumors, clonogenic survival of monolayer‐cultured tumor cells historically has been considered an appropriate endpoint but it is evident that this endpoint has limitations as it does not account for effects due to tumor vasculature, stimulation of immune responses, and more generally, the tumor microenvironment that may impact tumor response to radiation. For normal tissues, with the growing realization that late tissue damage in response to radiation is complex and can involve chronic oxidative stress and inflammation as well as damage to vasculature, it seems clear that additional studies are needed to determine whether or not clonogenic cell survival is a relevant endpoint for determining the RBE for early or late normal tissue response. The relevance of RBE values for clonogenic cell survival to cancer induction is also highly debatable .…”

Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases

“…Although it has been extensively implicated in the pathogenesis of age-related CVDs (82, 84–88), the role of endothelial cell senescence in radiation-induced CVDs has yet to be determined (89–91). Radiation-induced CVDs may be in part attributable to a combination of effects on microvasculature and macrovasculature (89–91).…”

“…Radiation-induced CVDs may be in part attributable to a combination of effects on microvasculature and macrovasculature (89–91). Senescent endothelial cells are incapable of regenerating new cells to maintain the homeostasis of vasculatures and repair damaged blood vessels, which may contribute to the decreased density of cardiac capillaries and small coronary arterioles and to the accelerated atherosclerosis of large blood vessels, including rodent and human coronary arteries (89, 90, 92–94). Moreover, senescent endothelial cells can potentially impede the angiogenic activity of endothelial progenitor cells via SASP and increased production of ROS.…”

Ionizing Radiation Increases Adhesiveness of Human Aortic Endothelial Cells via a Chemokine-Dependent Mechanism

“…It has been previously reported that endothelial cells were shown to be highly responsive to radiation exposure (51)(52)(53)(54)(55)(56)(57)(58)(59). Capillaries, which are not protected by other vascular tissues like smooth muscle cells, are believed to be more sensitive to acute radiation exposure compared to endothelium from larger vessels (60,61).…”