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Chongyu Su, Kang Shi, Xu Cheng, Yi Han, Yunsong Li, Daping Yu, Zhidong Liu
Our main objective is probing the effect of methylation of CLEC14A on its expression and lung adenocarcinoma (LUAD) progression. Microarray analysis was utilized to screen out differentially downregulated genes with hypermethylation in LUAD tissues. The CLEC14A expression level was measured by western blot analysis and qRT-PCR. Methylation-specific-PCR was performed to evaluate methylation status of CLEC14A. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromid (MTT) assay was used to check the relation between CLEC14A expression and cell proliferation...
March 2019: Journal of Cellular Physiology
Matteo Bocci, Jonas Sjölund, Ewa Kurzejamska, David Lindgren, Nour-Al-Dain Marzouka, Michael Bartoschek, Mattias Höglund, Kristian Pietras
Cancer cells sustain their metabolic needs through nutrients and oxygen supplied by the bloodstream. The requirement for tumor angiogenesis has been therapeutically exploited in the clinical setting mainly by means of inhibition of the vascular endothelial growth factor family of ligands and receptors. Despite promising results in preclinical models, the benefits for patients proved to be limited. Inadequate efficacy similarly halted the development of agents impinging on the activity of the activin receptor-like kinase (ALK)1, a member of the transforming growth factor-β superfamily...
August 21, 2018: Angiogenesis
Taek-Keun Kim, Chang Sik Park, Jihye Jang, Mi Ra Kim, Hee-Jun Na, Kangseung Lee, Hyun Jung Kim, Kyun Heo, Byong Chul Yoo, Young-Myeong Kim, Je-Wook Lee, Su Jin Kim, Eun Sung Kim, Dae Young Kim, Kiweon Cha, Tae Gyu Lee, Sukmook Lee
The C-type lectin-like domain of CLEC14a (CLEC14a-C-type lectin-like domain [CTLD]) is a key domain that mediates endothelial cell-cell contacts in angiogenesis. However, the role of CLEC14a-CTLD in pathological angiogenesis has not yet been clearly elucidated. In this study, through complementarity-determining region grafting, consecutive deglycosylation, and functional isolation, we generated a novel anti-angiogenic human monoclonal antibody that specifically targets CLEC14a-CTLD and that shows improved stability and homogeneity relative to the parental antibody...
March 2018: Molecular Oncology
Jihye Jang, Mi Ra Kim, Taek-Keun Kim, Woo Ran Lee, Jong Heon Kim, Kyun Heo, Sukmook Lee
CLEC14a (C-type lectin domain family 14 member) is a tumor endothelial cell marker protein that is known to play an important role in tumor angiogenesis, but the basic molecular mechanisms underlying this function have not yet been clearly elucidated. In this study, using various proteomic tools, we isolated a 70-kDa protein that interacts with the C-type lectin-like domain of CLEC14a (CLEC14a-CTLD) and identified it as heat shock protein 70-1A (HSP70-1A). Co-immunoprecipitation showed that HSP70-1A and CLEC14a interact on endothelial cells...
September 6, 2017: Scientific Reports
K A Khan, A J Naylor, A Khan, P J Noy, M Mambretti, P Lodhia, J Athwal, A Korzystka, C D Buckley, B E Willcox, F Mohammed, R Bicknell
The C-type lectin domain containing group 14 family members CLEC14A and CD93 are proteins expressed by endothelium and are implicated in tumour angiogenesis. CD248 (alternatively known as endosialin or tumour endothelial marker-1) is also a member of this family and is expressed by tumour-associated fibroblasts and pericytes. Multimerin-2 (MMRN2) is a unique endothelial specific extracellular matrix protein that has been implicated in angiogenesis and tumour progression. We show that the group 14 C-type lectins CLEC14A, CD93 and CD248 directly bind to MMRN2 and only thrombomodulin of the family does not...
November 2, 2017: Oncogene
Jiang Du, Qifen Yang, Lingfei Luo, Deqin Yang
Angiogenesis plays central role in the formation of functional circulation system. Characterizations of the involved factors and signaling pathways remain to be the key interest in the angiogenesis research. In this report, we showed that c1qr/cd93 and c1qrl/clec14a are specifically expressed in the vascular endothelial cells during zebrafish development. Single mutation of c1qr or c1qrl is associated with slightly malformation of inter-segmental vessels (ISVs), whereas double mutant exhibits severe defects in the ISVs formation without affecting early vasculogenesis...
January 29, 2017: Biochemical and Biophysical Research Communications
Sungwoon Lee, Seung-Sik Rho, Hyojin Park, Jeong Ae Park, Jihye Kim, In-Kyu Lee, Gou Young Koh, Naoki Mochizuki, Young-Myeong Kim, Young-Guen Kwon
Controlled angiogenesis and lymphangiogenesis are essential for tissue development, function, and repair. However, aberrant neovascularization is an essential pathogenic mechanism in many human diseases, including diseases involving tumor growth and survival. Here, we have demonstrated that mice deficient in C-type lectin family 14 member A (CLEC14A) display enhanced angiogenic sprouting and hemorrhage as well as enlarged jugular lymph sacs and lymphatic vessels. CLEC14A formed a complex with VEGFR-3 in endothelial cells (ECs), and CLEC14A KO resulted in a marked reduction in VEGFR-3 that was concomitant with increases in VEGFR-2 expression and downstream signaling...
February 1, 2017: Journal of Clinical Investigation
Brice Nativel, Audrey Figuester, Jessica Andries, Cynthia Planesse, Joël Couprie, Philippe Gasque, Wildriss Viranaicken, Thomas Iwema
CD93 belongs to the group XIV C-type lectin like domain (CTLD) and is closely related to thrombomodulin (CD141). Although CD93 is known to be involved in the regulation of cell adhesion and phagocytosis, its role in innate immunity remains to be fully investigated. Critically, published data about CD141 suggest that CD93 CTLD could be involved in the control of inflammation. In order to address further functional and structural analyses, we expressed human CD93 CTLD with several disulfide bonds in an E. coli expression system...
December 2016: Journal of Immunological Methods
S Krishna Priya, Kishore Kumar, K R Hiran, M R Bindhu, Rohit P Nagare, D K Vijaykumar, T S Ganesan
OBJECTIVE: The purpose of this study was to evaluate microvessel density (MVD) as assessed by C-type lectin 14A (CLEC14A), which is a new marker for endothelial cells, and compare its expression to CD31 and CD105 in epithelial ovarian cancer (EOC). METHODS: MVD was evaluated in tumors (n = 50) from patients with EOC who underwent primary surgery and in patients with EOC who received preoperative chemotherapy (n = 49) using immunohistochemistry with antibodies to CLEC14A, CD31 and CD105...
February 2017: International Journal of Clinical Oncology
Peter J Noy, Rajeeb K Swain, Kabir Khan, Puja Lodhia, Roy Bicknell
C-type lectin family 14, member A (CLEC14A), is a single-pass transmembrane glycoprotein that is overexpressed in tumor endothelial cells, and it promotes sprouting angiogenesis and modulates endothelial function via interactions with extracellular matrix proteins. Here, we show that CLEC14A is cleaved by rhomboid-like protein 2 (RHBDL2), one of 3 catalytic mammalian rhomboid-like (RHBDL) proteases, but that it is not cleaved by RHBDL1 or -3. Site-directed mutagenesis identified the precise site at which RHBDL2 cleaves CLEC14A, and targeted, small interfering RNAs that knockdown endogenous CLEC14A and RHBDL2 in human endothelial cells validated the specificity of CLEC14A shedding by RHBDL2...
June 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
P J Noy, P Lodhia, K Khan, X Zhuang, D G Ward, A R Verissimo, A Bacon, R Bicknell
We previously identified CLEC14A as a tumour endothelial marker. Here we show that CLEC14A is a regulator of sprouting angiogenesis in vitro and in vivo. Using a human umbilical vein endothelial cell spheroid-sprouting assay, we found CLEC14A to be a regulator of sprout initiation. Analysis of endothelial sprouting in aortic ring and in vivo subcutaneous sponge assays from clec14a(+/+) and clec14a(-/-) mice revealed defects in sprouting angiogenesis in CLEC14A-deficient animals. Tumour growth was retarded and vascularity reduced in clec14a(-/-) mice...
November 19, 2015: Oncogene
Patrizia Mancuso, Angelica Calleri, Giuliana Gregato, Valentina Labanca, Jessica Quarna, Pierluigi Antoniotti, Lucia Cuppini, Gaetano Finocchiaro, Marica Eoli, Vittorio Rosti, Francesco Bertolini
BACKGROUND: The endothelium is not a homogeneous organ. Endothelial cell heterogeneity has been described at the level of cell morphology, function, gene expression, and antigen composition. As a consequence of the genetic, transcriptome and surrounding environment diversity, endothelial cells from different vascular beds have differentiated functions and phenotype. Detection of circulating endothelial cells (CECs) by flow cytometry is an approach widely used in cancer patients, and their number, viability and kinetic is a promising tool to stratify patient receiving anti-angiogenic treatment...
2014: PloS One
Nicolas Delcourt, Celia Quevedo, Christelle Nonne, Pierre Fons, Donogh O'Brien, Denis Loyaux, Maria Diez, François Autelitano, Jean-Claude Guillemot, Pascual Ferrara, Arantza Muriana, Carlos Callol, Jean-Pascal Hérault, Jean-Marc Herbert, Gilles Favre, Françoise Bono
The formation of new vessels in the tumor, termed angiogenesis, is essential for primary tumor growth and facilitates tumor invasion and metastasis. Hypoxia has been described as one trigger of angiogenesis. Indeed, hypoxia, which is characterized by areas of low oxygen levels, is a hallmark of solid tumors arising from an imbalance between oxygen delivery and consumption. Hypoxic conditions have profound effects on the different components of the tumoral environment. For example, hypoxia is able to activate endothelial cells, leading to angiogenesis but also thereby initiating a cascade of reactions involving neutrophils, smooth muscle cells, and fibroblasts...
February 6, 2015: Journal of Biological Chemistry
Sara Zanivan, Federica Maione, Marco Y Hein, Juan Ramon Hernández-Fernaud, Pawel Ostasiewicz, Enrico Giraudo, Matthias Mann
Proteomics has been successfully used for cell culture on dishes, but more complex cellular systems have proven to be challenging and so far poorly approached with proteomics. Because of the complexity of the angiogenic program, we still do not have a complete understanding of the molecular mechanisms involved in this process, and there have been no in depth quantitative proteomic studies. Plating endothelial cells on matrigel recapitulates aspects of vessel growth, and here we investigate this mechanism by using a spike-in SILAC quantitative proteomic approach...
December 2013: Molecular & Cellular Proteomics: MCP
M K Ki, M H Jeoung, J R Choi, S-S Rho, Y-G Kwon, H Shim, J Chung, H J Hong, B D Song, S Lee
It has been suggested that clec14a may be involved in tumor angiogenesis. However, a molecular mechanism has not been clearly identified. In this study, we show for the first time that C-type lectin-like domain (CTLD) of clec14a may be important for regulating cell migration and filopodia formation. Using phage display technology, recombinant human antibodies specific to the CTLDs of human and mouse clec14a (clec14a-CTLD (immunoglobulin G) IgG) were selected. Functional assays using the antibodies showed that clec14a-CTLD IgGs specifically blocked endothelial cell migration and tube formation without affecting cell viability or activation...
November 28, 2013: Oncogene
Xiaodong Zhuang, Darren Cross, Victoria L Heath, Roy Bicknell
We have in recent years described several endothelial-specific genes that mediate cell migration. These include Robo4 (roundabout 4), CLEC14A (C-type lectin 14A) and ECSCR (endothelial cell-specific chemotaxis regulator) [formerly known as ECSM2 (endothelial cell-specific molecule 2)]. Loss of laminar shear stress induces Robo4 and CLEC14A expression and an endothelial 'tip cell' phenotype. Low shear stress is found not only at sites of vascular occlusion such as thrombosis and embolism, but also in the poorly structured vessels that populate solid tumours...
December 2011: Biochemical Society Transactions
M Mura, R K Swain, X Zhuang, H Vorschmitt, G Reynolds, S Durant, J F J Beesley, J M J Herbert, H Sheldon, M Andre, S Sanderson, K Glen, N-T Luu, H M McGettrick, P Antczak, F Falciani, G B Nash, Z S Nagy, R Bicknell
Tumor endothelial markers (TEMs) that are highly expressed in human tumor vasculature compared with vasculature in normal tissue hold clear therapeutic potential. We report that the C-type lectin CLEC14A is a novel TEM. Immunohistochemical and immunofluorescence staining of tissue arrays has shown that CLEC14A is strongly expressed in tumor vasculature when compared with vessels in normal tissue. CLEC14A overexpression in tumor vessels was seen in a wide range of solid tumor types. Functional studies showed that CLEC14A induces filopodia and facilitates endothelial migration, tube formation and vascular development in zebrafish that is, CLEC14A regulates pro-angiogenic phenotypes...
January 19, 2012: Oncogene
Seung-Sik Rho, Hyun-Jung Choi, Jeong-Ki Min, Heon-Woo Lee, Hongryeol Park, Hyojin Park, Young-Myeong Kim, Young-Guen Kwon
Clec14a is a member of the thrombomodulin (TM) family, but its function has not yet been determined. Here, we report that Clec14a is a plasma membrane protein of endothelial cells (ECs) expressed specifically in the vasculature of mice. Deletion mutant analysis revealed that Clec14a mediates cell-cell adhesion through its C-type lectin-like domain. Knockdown of Clec14a in ECs suppressed cell migratory activity and filopodial protrusion, and delayed formation of tube-like structures. These findings demonstrate that Clec14a is a novel EC-specific protein that appears to play a role in cell-cell adhesion and angiogenesis...
January 7, 2011: Biochemical and Biophysical Research Communications
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