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Distinctive properties of endothelial cells from tumor and normal tissue in human breast cancer

ABSTRACT: Tumor microenvironment shapes aggressiveness and is largely maintained by the conditions of angiogenesis formation. Thus endothelial cells (ECs) biological reactions are crucial to know and control the design of efficient therapies. Here we used a model of ECs representative for the breast cancer tumor site and the same but healthy organ. Cells characterization was performed at the transcriptome, protein expression levels and assessment of their functional biological responses: angiogenesis and permeability. We showed that the expression of proteins specific for ECs (ACE+, VWF+), their differentiation (CD31+, CD 133+, CD105+, CD34-), adhesion properties (ICAM-1+, VCAM-1+, CD62-L+), barrier formation (ZO-1+) were down-regulated in tumor-derived ECs. The NGS-based differential transcriptome analysis confirmed CD31-lowered expression and pointed to the increase of Ephrin-B2 and SNCAIP indicative for dedifferentiation. Functional assays confirmed these differences as angiogenesis was impaired while permeability increased in tumor-derived ECs, further validated by the distinct enhanced VEGF production in response to hypoxia, reflecting the tumor conditions. This work shows that endothelial cells differ highly significantly, both phenotypically and functionally in the tumor site vs. the normal corresponding tissue, influencing the tumor microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179509 | GEO | 2022/07/05

REPOSITORIES: GEO

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Gene expression analysis in control and HIF-2 alpha deficient murine lung endothelial cells under hypoxia

Project description:Journal : Blood. 2009 Jul 9;114(2):469-77. Epub 2009 May 13. Title : Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Authors : Skuli N, Liu L, Runge A, Wang T, Yuan L, Patel S, Iruela-Arispe L, Simon MC, Keith B. Abstract : Hypoxia-inducible factor-2alpha (HIF-2alpha) is highly expressed in embryonic vascular endothelial cells (ECs) and activates the expression of target genes whose products modulate vascular function and angiogenesis. In this report, we describe a genetic model designed to test the physiologic consequences of deleting HIF-2alpha in murine endothelial cells. Surprisingly, mice with HIF-2alpha-deficient ECs developed normally but displayed a variety of phenotypes, including increased vessel permeability, aberrant endothelial cell ultrastructure, and pulmonary hypertension. Moreover, these animals exhibited defective tumor angiogenesis associated with increased hypoxic stress and tumor cell apoptosis. Immortalized HIF-2alpha-deficient ECs displayed decreased adhesion to extracellular matrix proteins and expressed reduced levels of transcripts encoding fibronectin, integrins, endothelin B receptor, angiopoietin 2, and delta-like ligand 4 (Dll4). Together, these data identify unique cell-autonomous functions for HIF-2alpha in vascular endothelial cells. Keywords: Murine lung endothelial cell study Cnt1,2 and 3 (Hif-2a floxed/floxed) cells were subjected to 0.5% oxygen treatment for 16hrs and KO1,2 and 3 (Hif-2a knockout) cells were subjected to 0.5% oxygen treatment for 16hrs.

2009-07-15 | E-GEOD-16067 | biostudies-arrayexpress

Gene expression analysis in control and HIF-2 alpha deficient murine lung endothelial cells under hypoxia

2009-07-15 | GSE16067 | GEO

Apelin absence in endothelial cells

Project description:First, transcriptome analysis of purified CD31+ endothelial cells (ECs) from VEGF-treated sprouting embryoid bodies showed angiogenesis as the top affected category when Apelin is not present. In addition, loss of Apelin resulted in the modulation of pathways in ECs related to vasculogenesis, cell adhesion and response to hypoxia. Ingenuity Pathway Analysis (IPA) further identified VEGFR pathway as the main upstream regulator affected in endothelial cells, closely followed by the TGFβ1 and TNF pathways, all reduced in the absence of Apelin. The most inhibited genes from the VEGFR pathway in the absence of Apelin are angiogenesis-related genes. Second, transcriptome analysis of CD31+/CD105+ ECs sorted from Apelin wild-type and Apln-depleted tumors found a significant decrease in processes associated with endothelial cell proliferation and angiogenesis in ECs sorted out of Apelin-depleted tumors using IPA. Further, IPA predicted a decrease in the adhesion of granulocytes and upstream regulator analysis showed that proteins of the TGF-superfamily, Inhibin-βA and TGF-β1, as well as C/EBP-alpha, β-Catenin, ErbB2 and EGFR are predicted to be inhibited upstream regulators in ECs isolated from Apelin-depleted tumors.

2019-05-27 | GSE100293 | GEO

Syntaxin 5 determines Weibel-Palade body size and Von Willebrand factor secretion by controlling Golgi architecture

Project description:Abstract Von Willebrand factor (VWF) is a multimeric hemostatic protein primarily synthesized in endothelial cells (ECs). VWF is stored in endothelial storage organelles, the Weibel-Palade bodies (WPBs), whose biogenesis strongly depends on VWF anterograde trafficking and Golgi architecture. Elongated WPB morphology is correlated to longer VWF strings with better adhesive properties. We previously identified the SNARE SEC22B, which is involved in anterograde ER-to-Golgi transport, as a novel regulator of WPB elongation. To elucidate novel determinants of WPB morphology we explored endothelial SEC22B interaction partners in a mass spectrometry-based approach, identifying the Golgi SNARE Syntaxin 5 (STX5). We established STX5 knockdown in ECs using shRNA-dependent silencing and analyzed WPB and Golgi morphology, using confocal and electron microscopy. STX5-depleted ECs exhibited extensive Golgi fragmentation and decreased WPB length, which was associated with reduced intracellular VWF levels, and impaired stimulated VWF secretion. However, the secretion incompetent organelles in shSTX5 cells maintained WPB markers such as Angiopoietin 2, P-selectin, Rab27A, and CD63. Taken together, our study has identified SNARE protein STX5 as a novel regulator of WPB biogenesis

2022-01-27 | PXD027516 | Pride

Suppression of ANGPTL4 Reprograms Endothelial Cell Metabolism and Inhibits Angiogenesis

Project description:Angiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4iEC), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.

2023-11-22 | GSE211128 | GEO

Gene expression profiling of endothelial cells derived from Foxo1(+/+) and Foxo1(-/-) ES cells in response to VEGF

Project description:VEGF induces elongation of endothelial cells (ECs) that are derived from wild-type (Foxo1(+/+)) ES cells. VEGF-induced EC elongation is an important process of angiogenesis. ECs derived from Foxo1(-/-) ES cells fail to elongate in response to VEGF. Gene expression profiling of wild-type and Foxo1(-/-) ECs in the presence or absence of VEGF stimulation identifies responsible genes that regulate EC elongation. One wild-type (Foxo1(+/+)) ES cell clone and one Foxo1(-/-) ES cell clone were used. ES cells were cultured on OP9 stromal cell layer in the presence or absence of VEGF (10 ng/ml). After 6.5 days, VE-cadherin+ CD31+ ECs were isolated by FACS and used for total RNA extraction. Three independent experiments were performed for each condition.

2016-02-16 | E-GEOD-76366 | biostudies-arrayexpress

Endothelial cell heterogeneity in pathological angiogenesis characterized by metabolic transcriptome diversity

Project description:Endothelial cell (EC) metabolism regulates angiogenesis and is an emerging target for anti-angiogenic therapy in tumor and choroidal neovascularization (CNV). In contrast to tumor ECs (TECs), CNV-ECs cannot be isolated for unbiased metabolic target discovery. Here we used scRNA-sequencing to profile 28,337 choroidal ECs (CECs) from mice to in silico distinguish healthy CECs from CNV-ECs. Trajectory inference suggested that CNV-ECs plastically upregulate genes in central carbon metabolism and collagen biosynthesis during differentiation from quiescent postcapillary venous ECs. CEC-tailored genome scale metabolic modeling predicted essentiality of SQLE and ALDH18A1 for proliferation and collagen production, respectively. Comparative analysis in TECs revealed more outspoken metabolic transcriptome heterogeneity in subtypes and consistent upregulation of SQLE and ALDH18A1 across tumor types. Inhibition of SQLE and ALDH18A1 reduced sprouting angiogenesis in vitro. These findings demonstrate the potential of integrated scRNA-seq analysis to identify angiogenic metabolic targets in disease ECs.

2020-06-25 | E-MTAB-8119 | biostudies-arrayexpress

SAGE analysis of human glomerular endothelial cell

Project description:Tissue from macroscopically healthy parts of nephrectomized kidneys. Endothelial cells were purified from the cell outgrowth of glomeruli twice using CD31 magnetic beads and cultured on fibronectin coated surface. Cells were not passaged more than eight times and stained with vWf, CD31, and after stimulation with TNF alpha also with CD62E/P.

2010-12-01 | GSE25760 | GEO

Transcriptomic signatures of individual cell types in cerebral cavernous malformation

Project description:Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on FACS sorted endothelial cells (ECs), pericytes, neuroglia and microglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. In addition, VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified VEGFA/VEGFR2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets.

2023-12-30 | GSE233210 | GEO

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Project description:<p>The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer. </p>

2020-06-29 | MTBLS1764 | MetaboLights

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