A Differential Role for CD248 (Endosialin) in PDGF-Mediated Skeletal Muscle Angiogenesis

Naylor, Amy; McGettrick, Helen M.; Maynard, William; May, Philippa L.; Barone, Francesca; Croft, Adam P.; Egginton, Stuart; Buckley, Christopher D.

doi:10.1371/journal.pone.0107146

Cited by 33 publications

(23 citation statements)

References 35 publications

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“…In most cases, perivascular staining was moderate to strong which is also in agreement with previous studies [19, 20]. Similar to the other tissue types examined, normal skeletal muscle demonstrated variable moderate staining of endothelial cells and strong perivascular cell staining, a finding that is consistent with those of Naylor, et al [29]. …”

Section: Resultssupporting

confidence: 91%

Novel antibody probes for the characterization of endosialin/TEM-1

et al. 2016

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Endosialin (Tumor Endothelial Marker-1 (TEM-1), CD248) is primarily expressed on pericytes of tumor-associated microvasculature, tumor-associated stromal cells and directly on tumors of mesenchymal origin, including sarcoma and melanoma. While the function of endosialin/TEM-1 is incompletely understood, studies have suggested a role in supporting tumor growth and invasion thus making it an attractive therapeutic target. In an effort to further understand its role in cancer, we previously developed a humanized anti-endosialin/TEM-1 monoclonal antibody (mAb), called ontuxizumab (MORAb-004) for testing in preclinical and clinical studies. We herein report on the generation of an extensive panel of recombinant endosialin/TEM-1 protein extracellular domain (ECD) fragments and novel mAbs against ECD motifs. The domain-specific epitopes were mapped against ECD sub-domains to identify those that can detect distinct structural motifs and can be potentially formatted as probes suitable for diagnostic and functional studies. A number of mAbS were shown to cross-react with the murine and human protein, potentially allowing their use in human animal models and corresponding clinical trials. In addition, pairing of several mAbs supported their use in immunoassays that can detect soluble endosialin/TEM-1 (sEND) in the serum of healthy subjects and cancer patients.

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Section: Resultssupporting

confidence: 91%

Novel antibody probes for the characterization of endosialin/TEM-1

et al. 2016

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“…28 We found that mice with SMC-specific Cxcr4 deficiency showed an increased aortic expression of vimentin, a synthetic marker induced by PDGF-BB 29 , and of CD248 (endosialin), which is involved in PDGF-mediated cellular effects and associated with a synthetic SMC phenotype (Figure 5G, Supplemental Figure 5R,S). 30,31 Moreover, staining for vimentin, CD248, CD68 and lipids (Nile red) revealed a higher prevalence of de-differentiated SMCs in plaque caps of these mice (Figure 5H). In vitro , both WNT3a and CXCL12 increased the expression of contractile markers ( Tagln, smoothelin, CNN1 ) in cultured hAoSMCs, whereas the expression of synthetic markers was reduced (for CD248 after WNT3A treatment, Figure 5I, Supplemental Figure 5T) or not altered (after CXCL12 treatment, Figure 5J, Supplemental Figure 5U), respectively.…”

Section: Resultsmentioning

confidence: 91%

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Döring¹,

Noels²,

Vorst³

et al. 2017

Circulation

147

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Background The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, particularly as the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. Methods We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (EC, BmxCreERT2-driven)-specific or smooth muscle cell (SMC, SmmhcCreERT2- or TaglnCre-driven)-specific-deficiency of CXCR4 in an apolipoprotein E-deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/β-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. Results The cell-specific deletion of CXCR4 in arterial ECs (n=12-15) or SMCs (n=13-24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/β-catenin-signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4-deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4-deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259,796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. Conclusions Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.

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“…Endosialin-deficient mice are, unless pathologically challenged, phenotypically normal (27), although they display some delay of developmental vascular remodeling caused by perturbed pericyte function (28,29). Earlier studies have reported no overt difference in the growth of subcutaneous tumors in wild-type and endosialin-deficient mice (27,28,30).…”

Section: Introductionmentioning

confidence: 99%

Endosialin-Expressing Pericytes Promote Metastatic Dissemination

et al. 2016

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Metastasis is a multistep process that is critically dependent on the interaction of metastasizing tumor cells with cells in the local microenvironment. Within this tumor stroma, vesselassociated pericytes and myofibroblasts share a number of traits, including the upregulated expression of the transmembrane receptor endosialin (CD248). Comparative experiments in wild-type and endosialin-deficient mice revealed that stromal endosialin does not affect primary tumor growth but strongly promotes spontaneous metastasis. Mechanistically, endosialin-expressing pericytes in the primary tumor facilitate distant site metastasis by promoting tumor cell intravasation in a cell contact-dependent manner, resulting in elevated numbers of circulating tumor cells. Corresponding to these preclinical experiments, in independent cohorts of primary human breast cancers, upregulated endosialin expression significantly correlates with increased metastasis and poorer patient survival. Together, the data demonstrate a critical role for endosialin-expressing primary tumor pericytes in mediating metastatic dissemination and identify endosialin as a promising therapeutic target in breast cancer. Cancer Res; 76(18); 5313-25. Ó2016 AACR.

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A Differential Role for CD248 (Endosialin) in PDGF-Mediated Skeletal Muscle Angiogenesis

Cited by 33 publications

References 35 publications

Novel antibody probes for the characterization of endosialin/TEM-1

Novel antibody probes for the characterization of endosialin/TEM-1

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Endosialin-Expressing Pericytes Promote Metastatic Dissemination

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