Mobilization of Circulating Vascular Progenitors in Cancer Patients Receiving External Beam Radiation in Response to Tissue Injury

Allan, David S.; Morgan, Scott C.; Birch, Paul; Yang, Lin; Halpenny, Mike; Gunanayagam, Angelo; Li, Yuhua; Eapen, Libni

doi:10.1016/j.ijrobp.2009.04.033

Cited by 12 publications

(10 citation statements)

References 16 publications

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“…Decreased matrix metalloproteinase-9 delivery by CD11b-positive bone marrow-derived myelomonocytic cells was shown to be responsible for the angiogenic blockade observed in irradiated tumors [63]. Furthermore, radiation was reported to mobilize bone marow-derived vascular progenitors [64] and CD11b + cells which recruit to irradiated sites to promote vessel formation though a vasculogenic mechanism [65]. In future studies it will be important to compare radiation effects on endothelial cells vs. tumor-infiltrating bone marrow-derived cells in deficient angiogenesis and vasculogenic rescue.…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy Suppresses Angiogenesis in Mice through TGF-βRI/ALK5-Dependent Inhibition of Endothelial Cell Sprouting

et al. 2010

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BackgroundRadiotherapy is widely used to treat cancer. While rapidly dividing cancer cells are naturally considered the main target of radiotherapy, emerging evidence indicates that radiotherapy also affects endothelial cell functions, and possibly also their angiogenic capacity. In spite of its clinical relevance, such putative anti-angiogenic effect of radiotherapy has not been thoroughly characterized. We have investigated the effect of ionizing radiation on angiogenesis using in vivo, ex vivo and in vitro experimental models in combination with genetic and pharmacological interventions.Principal FindingsHere we show that high doses ionizing radiation locally suppressed VEGF- and FGF-2-induced Matrigel plug angiogenesis in mice in vivo and prevented endothelial cell sprouting from mouse aortic rings following in vivo or ex vivo irradiation. Quiescent human endothelial cells exposed to ionizing radiation in vitro resisted apoptosis, demonstrated reduced sprouting, migration and proliferation capacities, showed enhanced adhesion to matrix proteins, and underwent premature senescence. Irradiation induced the expression of P53 and P21 proteins in endothelial cells, but p53 or p21 deficiency and P21 silencing did not prevent radiation-induced inhibition of sprouting or proliferation. Radiation induced Smad-2 phosphorylation in skin in vivo and in endothelial cells in vitro. Inhibition of the TGF-β type I receptor ALK5 rescued deficient endothelial cell sprouting and migration but not proliferation in vitro and restored defective Matrigel plug angiogenesis in irradiated mice in vivo. ALK5 inhibition, however, did not rescue deficient proliferation. Notch signaling, known to hinder angiogenesis, was activated by radiation but its inhibition, alone or in combination with ALK5 inhibition, did not rescue suppressed proliferation.ConclusionsThese results demonstrate that irradiation of quiescent endothelial cells suppresses subsequent angiogenesis and that ALK5 is a critical mediator of this suppression. These results extend our understanding of radiotherapy-induced endothelial dysfunctions, relevant to both therapeutic and unwanted effects of radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Radiotherapy Suppresses Angiogenesis in Mice through TGF-βRI/ALK5-Dependent Inhibition of Endothelial Cell Sprouting

et al. 2010

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“…Several studies have reported changes in specific populations of EPCs after vascular trauma/injury (Table 2). Circulating EPCs are elevated in patients who experience burns, coronary artery bypass [59], congestive heart failure [60], musculoskeletal trauma [61], head and neck cancer [62], hind limb ischemia [63], radiation therapy [64], coronary angioplasty [65], or surgical injury (laparotomy) [66]. However, the surface markers used to identify EPCs in each study vary widely, emphasizing the controversy that exists in the field in terms of the characteristics of EPCs (Table 2).…”

Section: Vasculature Effects Of Wbrtmentioning

confidence: 99%

Whole Brain Radiation-Induced Vascular Cognitive Impairment: Mechanisms and Implications

Warrington

Ashpole

Csiszár³

et al. 2013

J Vasc Res

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Mild cognitive impairment is a well-documented consequence of whole brain radiation therapy (WBRT) that affects 40-50% of long-term brain tumor survivors. The exact mechanisms for the decline in cognitive function after WBRT remain elusive and no treatment or preventative measures are available for use in the clinic. Here, we review recent findings indicating how changes in the neurovascular unit may contribute to the impairments in learning and memory. In addition to affecting neuronal development, WBRT induces profound capillary rarefaction within the hippocampus - a region of the brain important for learning and memory. Therapeutic strategies such as hypoxia, which restore the capillary density, result in the rescue of cognitive function. In addition to decreasing vascular density, WBRT impairs vasculogenesis and/or angiogenesis, which may also contribute to radiation-induced cognitive decline. Further studies aimed at uncovering the specific mechanisms underlying these WBRT-induced changes in the cerebrovasculature are essential for developing therapies to mitigate the deleterious effects of WBRT on cognitive function.

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“…Interestingly, in conditions of acute vascular ischemia and EC injury, an increase in the number of circulating CD34 ϩ / KDR ϩ cells has been observed (eg, thermal injury, 19 radiation-induced endothelial injury, 20 sepsis, 21 acute ischemic stroke, 22 acute myocardial infarction, 23 and even brief exposure to second-hand smoke 24 ). Some of these studies reported that the acute elevation of circulating CD34 ϩ /KDR ϩ cells was associated with a concomitant increase in levels of mobilizing factors, such as VEGF and SDF-1, suggesting a causal relationship.…”

Section: 19%ϯ018% Of the Mobilized Peripheral Cd34mentioning

confidence: 99%

Human CD34 ⁺ /KDR ⁺ Cells Are Generated From Circulating CD34 ⁺ Cells After Immobilization on Activated Platelets

Boer

Hovens²,

Oeveren‐Rietdijk³

et al. 2011

ATVB

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Mobilization of Circulating Vascular Progenitors in Cancer Patients Receiving External Beam Radiation in Response to Tissue Injury

Cited by 12 publications

References 16 publications

Radiotherapy Suppresses Angiogenesis in Mice through TGF-βRI/ALK5-Dependent Inhibition of Endothelial Cell Sprouting

Radiotherapy Suppresses Angiogenesis in Mice through TGF-βRI/ALK5-Dependent Inhibition of Endothelial Cell Sprouting

Whole Brain Radiation-Induced Vascular Cognitive Impairment: Mechanisms and Implications

Human CD34 ⁺ /KDR ⁺ Cells Are Generated From Circulating CD34 ⁺ Cells After Immobilization on Activated Platelets

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Mobilization of Circulating Vascular Progenitors in Cancer Patients Receiving External Beam Radiation in Response to Tissue Injury

Cited by 12 publications

References 16 publications

Radiotherapy Suppresses Angiogenesis in Mice through TGF-βRI/ALK5-Dependent Inhibition of Endothelial Cell Sprouting

Radiotherapy Suppresses Angiogenesis in Mice through TGF-βRI/ALK5-Dependent Inhibition of Endothelial Cell Sprouting

Whole Brain Radiation-Induced Vascular Cognitive Impairment: Mechanisms and Implications

Human CD34 + /KDR + Cells Are Generated From Circulating CD34 + Cells After Immobilization on Activated Platelets

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Human CD34 ⁺ /KDR ⁺ Cells Are Generated From Circulating CD34 ⁺ Cells After Immobilization on Activated Platelets