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Endothelial perturbations and therapeutic strategies in normal tissue radiation damage.

Korpela E, Liu SK - Radiat Oncol (2014)

Bottom Line: 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.Endothelial cell targeted therapies that protect against such endothelial cell perturbations and the development of acute normal tissue damage are mostly under preclinical development.

View Article: PubMed Central - PubMed

Affiliation: Biological Sciences, Sunnybrook Research Institute and Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, M4N 3M5, Canada. elina.korpela@mail.utoronto.ca.

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.

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Related in: MedlinePlus

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.
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Fig1: 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.

Mentions: The microvasculature is emerging as a biologically targetable compartment in the field of normal tissue radiation protection during RT. On the whole, preclinical radiation damage models support the notion that EC perturbations following irradiation contribute to the developing acute injury. The concept of the microvasculature as a mediator of acute radiation damage is illustrated in FigureĀ 1. Conflicting findings may be attributed to the unique limitations of experimental methodologies or differing contexts of microvascular ECs in distinct organs. Indeed, it is known that ECs are diverse in their molecular responses and characteristics [105,106]. Additionally, it is conceivable that the tumor microenvironment could influence the response of normal tissue vasculature to irradiation [9,107], and thus future studies should account for this possibility.Figure 1


Endothelial perturbations and therapeutic strategies in normal tissue radiation damage.

Korpela E, Liu SK - Radiat Oncol (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4279961&req=5

Fig1: 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.
Mentions: The microvasculature is emerging as a biologically targetable compartment in the field of normal tissue radiation protection during RT. On the whole, preclinical radiation damage models support the notion that EC perturbations following irradiation contribute to the developing acute injury. The concept of the microvasculature as a mediator of acute radiation damage is illustrated in FigureĀ 1. Conflicting findings may be attributed to the unique limitations of experimental methodologies or differing contexts of microvascular ECs in distinct organs. Indeed, it is known that ECs are diverse in their molecular responses and characteristics [105,106]. Additionally, it is conceivable that the tumor microenvironment could influence the response of normal tissue vasculature to irradiation [9,107], and thus future studies should account for this possibility.Figure 1

Bottom Line: 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.Endothelial cell targeted therapies that protect against such endothelial cell perturbations and the development of acute normal tissue damage are mostly under preclinical development.

View Article: PubMed Central - PubMed

Affiliation: Biological Sciences, Sunnybrook Research Institute and Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, M4N 3M5, Canada. elina.korpela@mail.utoronto.ca.

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.

Show MeSH
Related in: MedlinePlus