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A function-blocking CD47 antibody modulates extracellular vesicle-mediated intercellular signaling between breast carcinoma cells and endothelial cells.

ABSTRACT: Tumor cells release extracellular vesicles (EVs) into the tumor microenvironment that may facilitate malignant progression and metastasis. Breast carcinoma EVs express high levels of the thrombospondin-1 and signal regulatory protein-? receptor CD47, which is the target of several experimental therapeutics currently in clinical trials. We analyzed changes in gene expression and function in human umbilical vein endothelial cells (HUVEC) induced by treatment with EVs derived from breast carcinoma cells and the effects of the function-blocking CD47 antibody B6H12 on the resulting intercellular communication. CD47+ EVs exhibited greater uptake by HUVEC compared to CD47- EVs, but the CD47 antibody did not inhibit their uptake. Global and targeted analyses of transcripts demonstrated that treatment of HUVEC with EVs derived from MDA-MB-231 breast carcinomas cells altered pathways associated with tumor necrosis factor-? signaling, angiogenesis, lymphangiogenesis, endothelial-mesenchymal transition, and extracellular matrix. EVs from triple-negative MDA-MB-231 cells were more active than EVs from less metastatic breast carcinoma cell lines. Treatment with MDA-MB-231 EVs down-regulated VEGFR2 mRNA expression and tyrosine phosphorylation while enhancing phosphorylation of the tyrosine phosphatase SHP2. VEGFR2 expression and phosphorylation in HUVEC was further inhibited by the CD47 antibody. Consistent with the observed changes in endothelial-mesenchymal transition genes and SHP2, treatment with MDA-MB-231-derived EVs decreased Zeb1 protein levels in HUVEC, whereas the CD47 antibody increased Zeb1 levels. The induction of E-selectin and other known targets of tumor necrosis factor-? signaling by EVs was also enhanced by the CD47 antibody, and E-selectin was the most up-regulated transcript following CD47 antibody treatment alone. These studies reveal several mechanisms by which therapeutics targeting CD47 could modulate tumor growth by altering the cross talk between cancer-derived EVs and nonmalignant cells in the tumor stroma.

SUBMITTER: Kaur S

PROVIDER: S-EPMC5842190 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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A function-blocking CD47 antibody modulates extracellular vesicle-mediated intercellular signaling between breast carcinoma cells and endothelial cells.

Kaur Sukhbir S Elkahloun Abdel G AG Singh Satya P SP Arakelyan Anush A Roberts David D DD

Journal of cell communication and signaling 20171129 1

Tumor cells release extracellular vesicles (EVs) into the tumor microenvironment that may facilitate malignant progression and metastasis. Breast carcinoma EVs express high levels of the thrombospondin-1 and signal regulatory protein-α receptor CD47, which is the target of several experimental therapeutics currently in clinical trials. We analyzed changes in gene expression and function in human umbilical vein endothelial cells (HUVEC) induced by treatment with EVs derived from breast carcinoma ...[more]

PMID: 29188480

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Project description:BackgroundExtracellular vesicles (EVs) contain bioactive cargo including miRNAs and proteins that are released by cells during cell-cell communication. Endothelial cells (ECs) form the innermost lining of all blood vessels, interfacing with cells in the circulation and vascular wall. It is unknown whether ECs release EVs capable of governing recipient cells within these 2 separate compartments. Given their boundary location, we propose ECs use bidirectional release of distinct EV cargo in quiescent (healthy) and activated (atheroprone) states to communicate with cells within the circulation and blood vessel wall.MethodsEVs were isolated from primary human aortic ECs (plate and transwell grown; ±IL [interleukin]-1β activation), quantified, visualized, and analyzed by miRNA transcriptomics and proteomics. Apical and basolateral EC-EV release was determined by miRNA transfer, total internal reflection fluorescence and electron microscopy. Vascular reprogramming (RNA sequencing) and functional assays were performed on primary human monocytes or smooth muscle cells±EC-EVs.ResultsActivated ECs increased EV release, with miRNA and protein cargo related to atherosclerosis. EV-treated monocytes and smooth muscle cells revealed activated EC-EV altered pathways that were proinflammatory and atherogenic. ECs released more EVs apically, which increased with activation. Apical and basolateral EV cargo contained distinct transcriptomes and proteomes that were altered by EC activation. Notably, activated basolateral EC-EVs displayed greater changes in the EV secretome, with pathways specific to atherosclerosis. In silico analysis determined compartment-specific cargo released by the apical and basolateral surfaces of ECs can reprogram monocytes and smooth muscle cells, respectively, with functional assays and in vivo imaging supporting this concept.ConclusionsDemonstrating that ECs are capable of polarized EV cargo loading and directional EV secretion reveals a novel paradigm for endothelial communication, which may ultimately enhance the design of endothelial-based therapeutics for cardiovascular diseases such as atherosclerosis where ECs are persistently activated.

Dataset Information

A function-blocking CD47 antibody modulates extracellular vesicle-mediated intercellular signaling between breast carcinoma cells and endothelial cells.

Publications

A function-blocking CD47 antibody modulates extracellular vesicle-mediated intercellular signaling between breast carcinoma cells and endothelial cells.

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