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-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 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-α 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-α 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.
journal_name
J Cell Commun Signaljournal_title
Journal of cell communication and signalingauthors
Kaur S,Elkahloun AG,Singh SP,Arakelyan A,Roberts DDdoi
10.1007/s12079-017-0428-0subject
Has Abstractpub_date
2018-03-01 00:00:00pages
157-170issue
1eissn
1873-9601issn
1873-961Xpii
10.1007/s12079-017-0428-0journal_volume
12pub_type
杂志文章abstract::Mice lacking the pro-adhesive matricellular protein connective tissue growth factor (CTGF/CCN2) display an embryonic lethal phenotype due to defects in bone and cartilage. However, the specific role of CCN2 in skin development is unknown. Here, we generated mice deleted for CCN2 in the entire body (using a cre/lox sys...
journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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更新日期:2012-12-01 00:00:00
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pub_type: 杂志文章,评审
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journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-015-0261-2
更新日期:2015-06-01 00:00:00
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journal_title:Journal of cell communication and signaling
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更新日期:2008-12-01 00:00:00
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-011-0156-9
更新日期:2012-03-01 00:00:00
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journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
doi:10.1007/s12079-017-0389-3
更新日期:2017-12-01 00:00:00
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
pub_type: 杂志文章
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journal_title:Journal of cell communication and signaling
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