The importance of the vascular endothelial barrier in the immune-inflammatory response induced by radiotherapy

Abstract

Altered by ionising radiation, the vascular network is considered as a prime target to limit normal tissue damage and improve tumour control in radiotherapy (RT). Irradiation damages and/or activates endothelial cells, which then participate in the recruitment of circulating cells, especially by overexpressing cell adhesion molecules, but also by other as yet unknown mechanisms. Radiation-induced lesions are associated with infiltration of immune-inflammatory cells from the blood and/or the lymph circulation. Damaged cells from the tissues and immune-inflammatory resident cells release factors that attract cells from the circulation, leading to the restoration of tissue balance by fighting against infection, elimination of damaged cells and healing of the injured area. In normal tissues that surround the tumours, the development of an immune-inflammatory reaction in response to radiation-induced tissue injury can turn out to be chronic and deleterious for the organ concerned, potentially leading to fibrosis and/or necrosis of the irradiated area. Similarly, tumours can elicit an immune-inflammation reaction, which can be initialised and amplified by cancer therapy such as radiotherapy, although immune checkpoints often allow many cancers to be protected by inhibiting the T-cell signal. Herein, we have explored the involvement of vascular endothelium in the fate of healthy tissues and tumours undergoing radiotherapy. This review also covers current investigations that take advantage of the radiation-induced response of the vasculature to spare healthy tissue and/or target tumours better.

Temporal clustering analysis of endothelial cell gene expression following exposure to a conventional radiotherapy dose fraction using Gaussian process clustering

“…The expression of BIRC5 decreased in the early times post-irradiation at 2 Gy, and then increased and finally returned to normal values, reflecting a possible wave of apoptosis or death followed by the activation of survival mechanisms. In contrast, BIRC5 was considerably down-regulated at 20 Gy, both for a single dose and for a fractionated dose, which is consistent with the low survival rate observed at these high doses [ 4 ]. Intriguingly, PTGS2 was found to be down-regulated at 2 Gy while up-regulated at 20 Gy at almost all the time points post-irradiation.…”

“…It also orchestrates wound healing in the case of radiation injury [ 3 ]. In the vasculature, the endothelium is considered as a promising target to improve the differential effect of RT in the future [ 4 , 5 ].…”

The Tumor Vascular Endothelium as Decision Maker in Cancer Therapy

“…The radiation sensitivity of vessels in general correlates with their morphology: capillaries and small vessels (like angiogenic tumor vessels) are extremely sensitive to ionizing radiation, whereas larger blood vessels seem to be less affected ( 96 , 97 ). Radiation induces phenotypic changes of tumor endothelial cells (e.g., apoptosis or senescence) as well as wide range of microenvironmental changes by production and secretion of reactive oxygen and nitrogen species, growth and chemotactic factors, which in turn govern recruitment of immune cells ( 11 , 98 , 99 ).…”

“…This complicates not only the efficient distribution of nutritions and oxygen but also the effective administration of cancer therapeutics. Even at the molecular level, i.e., regarding the expression of important signaling molecules, receptors or cell adhesion molecules in the tumor vascular bed, there is an imbalanced state between pro- and anti-oxidants, -inflammatory molecules, and -coagulation signals ( 9 – 11 ). As a result, tumor endothelial cells bear immune-regulatory properties: alterations in the immune cell attraction and activation, as well as in the expression of co-stimulatory and -inhibitory molecules can promote immune tolerance and thus generate an immune-privileged tumor microenvironment ( 12 – 14 ).…”

Shared Features of Endothelial Dysfunction between Sepsis and Its Preceding Risk Factors (Aging and Chronic Disease)

“…Anticancer chemotherapy may induce systemic damage of vascular endothelium related to massive cell loss and alterations of endothelial function [ 40 ]. Radiotherapy causes premature senescence, apoptosis of endothelial cells and increased vascular permeability [ 41 ]. Endothelial barrier is also altered in cardiovascular disease.…”