In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury

Rannou, Emilie; François, Agnès; Toullec, Aurore; Guipaud, Olivier; Buard, Valérie; Tarlet, Georges; Mintet, Elodie; Jaillet, Cyprien; Iruela‐Arispe, M. Luisa; Benderitter, Marc; Sabourin, Jean‐Christophe; Milliat, Fabien

doi:10.1038/srep15738

Cited by 50 publications

(48 citation statements)

References 42 publications

(50 reference statements)

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“…cDNA (400 ng) per sample was loaded onto the port of each gene signature array card and PCR was performed with the ABI PRISM 7900 Sequence detection system (Applied Biosystems). Analyses were conducted according to the procedure previously described in detail [ 47 ]. Data Assist software (Applied Biosystems) was used to determine fold changes, with fixed criteria: a maximum allowable Ct value at 37 was fixed and maximum Ct values were not included in calculations.…”

Section: Methodsmentioning

confidence: 99%

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

Heinonen¹,

Milliat²,

Benadjaoud³

et al. 2018

PLoS ONE

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The vascular endothelium is considered as a key cell compartment for the response to ionizing radiation of normal tissues and tumors, and as a promising target to improve the differential effect of radiotherapy in the future. Following radiation exposure, the global endothelial cell response covers a wide range of gene, miRNA, protein and metabolite expression modifications. Changes occur at the transcriptional, translational and post-translational levels and impact cell phenotype as well as the microenvironment by the production and secretion of soluble factors such as reactive oxygen species, chemokines, cytokines and growth factors. These radiation-induced dynamic modifications of molecular networks may control the endothelial cell phenotype and govern recruitment of immune cells, stressing the importance of clearly understanding the mechanisms which underlie these temporal processes. A wide variety of time series data is commonly used in bioinformatics studies, including gene expression, protein concentrations and metabolomics data. The use of clustering of these data is still an unclear problem. Here, we introduce kernels between Gaussian processes modeling time series, and subsequently introduce a spectral clustering algorithm. We apply the methods to the study of human primary endothelial cells (HUVECs) exposed to a radiotherapy dose fraction (2 Gy). Time windows of differential expressions of 301 genes involved in key cellular processes such as angiogenesis, inflammation, apoptosis, immune response and protein kinase were determined from 12 hours to 3 weeks post-irradiation. Then, 43 temporal clusters corresponding to profiles of similar expressions, including 49 genes out of 301 initially measured, were generated according to the proposed method. Forty-seven transcription factors (TFs) responsible for the expression of clusters of genes were predicted from sequence regulatory elements using the MotifMap system. Their temporal profiles of occurrences were established and clustered. Dynamic network interactions and molecular pathways of TFs and differential genes were finally explored, revealing key node genes and putative important cellular processes involved in tissue infiltration by immune cells following exposure to a radiotherapy dose fraction.

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Section: Methodsmentioning

confidence: 99%

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

Heinonen¹,

Milliat²,

Benadjaoud³

et al. 2018

PLoS ONE

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“…Tumor eradication or local cancer control for a better outcome are the main goals of radiation therapy. Endothelial cells act as critical determinants of the radiation response in tumors as radiotherapy generally fosters endothelial apoptosis, increased vascular permeability, and acquisition of a pro-inflammatory and -coagulant phenotype ( 93 – 95 ). 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 ).…”

Section: Tumor Endothelium Mediated Immunological Consequences In Thementioning

confidence: 99%

The Tumor Vascular Endothelium as Decision Maker in Cancer Therapy

2018

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Genetic and pathophysiologic criteria prearrange the uncontrolled growth of neoplastic cells that in turn initiates new vessel formation, which is prerequisite for further tumor growth and progression. This first endothelial lining is patchy, disordered in structure and thus, angiogenic tumor vessels were proven to be functionally inferior. As a result, tumors were characterized by areas with an apparent oversupply in addition to areas with an undersupply of vessels, which complicates an efficient administration of intravenous drugs in cancer therapy and might even lower the response e.g. of radiotherapy (RT) because of the inefficient oxygen supply. In addition to the vascular dysfunction, tumor blood vessels contribute to the tumor escape from immunity by the lack of response to inflammatory activation (endothelial anergy) and by repression of leukocyte adhesion molecule expression. However, tumor vessels can remodel by the association with and integration of pericytes and smooth muscle cells which stabilize these immature vessels resulting in normalization of the vascular structures. This normalization of the tumor vascular bed could improve the efficiency of previously established therapeutic approaches, such as chemo- or radiotherapy by a more homogenous drug and oxygen distribution, and/or by overcoming endothelial anergy. This review highlights the current investigations that take advantage of a proper vascular function for improving cancer therapy with a special focus on the endothelial-immune system interplay.

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“…For example, prevention of endothelial apoptosis by inhibiting the enzyme acid sphingomyelinase and pro-apoptotic sphingolipid ceramide (5, 32), suppression of endothelial specific PAR-1 activation (a thrombin receptor and an essential mediator of vascular diseases) (6, 33) and inhibition of leucocyte attachment with endothelium by systemic administration of antioxidant enzyme superoxide dismutase (34) confer significant protection against radiation-induced intestinal epithelial cell apoptosis in mice. These studies suggest that maintaining normal endothelial functions in the intestinal microvasculature is crucial to limiting acute radiation enteropathy.…”

Section: Discussionmentioning

confidence: 99%

“…proposed that radiation-induced endothelial dysfunction leads to inflammation, oxidative stress and enhanced TGF-β production, which in turn, suppress epithelial cell proliferation, causing depletion of epithelial cells, and finally resulting in breakdown of the epithelial barrier (4). Other experimental findings demonstrate that safeguarding endothelial cells from radiation injury confers protection of the intestinal epithelium (5, 6), indicating the potential role of endothelial cells in the pathogenesis of intestinal toxicity.…”

Section: Introductionmentioning

confidence: 98%

Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model

Pathak¹,

Wang²,

Garg³

et al. 2016

Radiation Research

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Intestinal radiation toxicity occurs during and after abdominopelvic radiotherapy. Endothelial cells play a significant role in modulating radiation-induced intestinal damage. We demonstrated that the endothelial cell surface receptor thrombomodulin (TM), a protein with anticoagulant, antiinflammatory and antioxidant properties, mitigates radiation-induced lethality in mice. The goal of this study was to determine whether recombinant TM (Solulin) can protect the intestine from toxicity in a clinically relevant rat model. A 4 cm loop of rat small bowel was exposed to fractionated 5 Gy X radiation for 9 consecutive days. The animals were randomly assigned to receive daily subcutaneous injections of vehicle or Solulin (3 mg/kg/day or 10 mg/kg/day) for 27 days starting 4 days before irradiation. Early intestinal injury was assessed two weeks after irradiation by quantitative histology, morphometry, immunohistochemistry and luminol bioluminescence imaging. Solulin treatment significantly ameliorated intestinal radiation injury, made evident by a decrease in myeloperoxidase (MPO) activity, transforming growth factor beta (TGF-β) immunoreactivity, collagen-I deposition, radiation injury score (RIS) and intestinal serosal thickening. These findings indicate the need for further development of Solulin as a prophylactic and/or therapeutic agent to mitigate radiation-induced intestinal damage.

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In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury

Cited by 50 publications

References 42 publications

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

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

The Tumor Vascular Endothelium as Decision Maker in Cancer Therapy

Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model

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