Identification and angiogenic role of the novel tumor endothelial marker CLEC14A

Mura, Manuela; Swain, Roy; Zhuang, Xiaodong; Vorschmitt, Henrik; Reynolds, Gary; Durant, Sarah M.; Beesley, James; Herbert, John; Sheldon, Helen; Andre, Maud; Sanderson, Sharon; Glen, Katie E.; Luu, Nguyet-Thin; McGettrick, Helen M.; Antczak, Philipp; Falciani, Francesco; Nash, Gerard B.; Nagy, Zsuzsanna; Bicknell, Roy

doi:10.1038/onc.2011.233

Cited by 95 publications

(159 citation statements)

References 44 publications

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“…Finally, regulatory mechanisms control undesired escalation of angiogenesis. Activation of antiangiogenic factors such as thrombospondin-1 (TSP1) and TSP2, or downregulation of proangiogenic factors such as angiotensin-converting enzyme or c-type lectin domain family 14 member A are involved here (51)(52)(53)(54). ECM reorganization is strongly interlinked with angiogenesis and related proteins were found regulated in both cell types as well.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Human Fibroblasts and Endothelial Cells to the Hallmarks of Inflammation as Determined by Proteome Profiling

Slany

Bileck

Kreutz

et al. 2016

Molecular & Cellular Proteomics

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In order to systematically analyze proteins fulfilling effector functionalities during inflammation, here we present a comprehensive proteome study of inflammatory activated primary human endothelial cells and fibroblasts. Cells were stimulated with interleukin 1-␤ and fractionated in order to obtain secreted, cytoplasmic and nuclear protein fractions. Proteins were submitted to a data-dependent bottom up analytical platform using a QExactive orbitrap and the MaxQuant software for protein identification and label-free quantification. Results were further combined with similarly generated data previously obtained from the analysis of inflammatory activated peripheral blood mononuclear cells. Applying a false discovery rate of less than 0.01 at both, peptide and protein level, a total of 8370 protein groups assembled from 117,599 peptides was identified; mass spectrometry data have been made fully accessible via ProteomeXchange with identifier PXD003406 to PXD003417. Comparative proteome analysis allowed us to determine common and cell type-specific inflammation signatures comprising novel candidate marker molecules and related expression patterns of transcription factors. Cardinal features of inflammation such as interleukin 1-␤ processing and the interferon response differed substantially between the investigated cells. Furthermore, cells also exerted similar inflammation-related tasks; however, by making use of different sets of proteins. Hallmarks of inflammation thus emerged, including angiogenesis, extracellular matrix reorganization, adaptive and innate immune responses, oxidative stress response, cell proliferation and differentiation, cell adhesion and migration in addition to monosaccharide metabolic processes, representing both, common and cell type-specific responsibilities of cells during inflammation. Molecular & Cellular

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Section: Discussionmentioning

confidence: 99%

Contribution of Human Fibroblasts and Endothelial Cells to the Hallmarks of Inflammation as Determined by Proteome Profiling

Slany

Bileck

Kreutz

et al. 2016

Molecular & Cellular Proteomics

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“…Interestingly, two other cell surface receptors that each have a single CTLD and confined to the tumor vasculature are being considered as molecular targets of antiangiogenics for indirect treatment of solid tumors. The first, CLEC14A (EGFR-5), is exclusively expressed by vascular endothelial cells and promotes cell-cell adhesion and neo-angiogenesis via its single CTLD (27)(28)(29). The second, endosialin (CD248, TEM-1), is expressed by stromal fibroblasts and pericytes and can promote tumor angiogenesis and growth (30,31).…”

Section: Discussionmentioning

confidence: 99%

Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

Rodriguez-Teja

Gronau

Minamidate

et al. 2015

Molecular Cancer Research

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Epithelial cell-cell contacts maintain normal glandular tissue homeostasis, and their breakage can trigger epithelialto-mesenchymal transition (EMT), a fundamental step in the development of metastatic cancer. Despite the ability of C-type lectin domains (CTLD) to modulate cell-cell adhesion, it is not known if they modulate epithelial adhesion in EMT and tumor progression. Here, the multi-CTLD mannose receptor, Endo180 (MRC2/uPARAP), was shown using the Kaplan-Meier analysis to be predictive of survival outcome in men with early prostate cancer. A proteomic screen of novel interaction partners with the fourth CTLD (CTLD4) in Endo180 revealed that its complex with CD147 is indispensable for the stability of three-dimensional acini formed by nontransformed prostate epithelial cells (PEC). Mechanistic study using knockdown of Endo180 or CD147, and treatment with an Endo180 mAb targeting CTLD4 (clone 39.10), or a dominant-negative GST-CTLD4 chimeric protein, induced scattering of PECs associated with internalization of Endo180 into endosomes, loss of E-cadherin (CDH1/ECAD), and unzipping of cell-cell junctions. These findings are the first to demonstrate that a CTLD acts as a suppressor and regulatory switch for EMT; thus, positing that stabilization of Endo180-CD147 complex is a viable therapeutic strategy to improve rates of prostate cancer survival.Implications: This study identifies the interaction between CTLD4 in Endo180 and CD147 as an EMT suppressor and indicates that stabilization of this molecular complex improves prostate cancer survival rates.

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“…C-type lectin family 14 member A (CLEC14A) is a type I transmembrane protein belonging to the C-type lectin superfamily that contains an EGF-like domain, along with the C-type lectin domain (8). The C-type lectin domain is a carbohydrate-binding protein domain that mediates many functions including cell-to-cell adhesion, inflammatory responses, and apoptosis (9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…To examine the effects of CLEC14A deficiency on EC sprouting and angiogenesis in the absence of confounding factors, we performed ex vivo aortic ring assays and Matrigel plug under hypoxic conditions as well as in circulating ECs of cancer patients (8,(16)(17)(18). Furthermore, CLEC14A regulates sprouting angiogenesis by shedding its ectodomain, which is catalyzed by rhomboid-like 2 protein (19).…”

Section: Introductionmentioning

confidence: 99%

Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

Lee

Rho

Park

et al. 2016

Journal of Clinical Investigation

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Identification and angiogenic role of the novel tumor endothelial marker CLEC14A

Cited by 95 publications

References 44 publications

Contribution of Human Fibroblasts and Endothelial Cells to the Hallmarks of Inflammation as Determined by Proteome Profiling

Contribution of Human Fibroblasts and Endothelial Cells to the Hallmarks of Inflammation as Determined by Proteome Profiling

Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

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