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Neoplasia. 2017 Nov;19(11):941-949. doi: 10.1016/j.neo.2017.06.007. Epub 2017 Sep 29.

Esophageal Adenocarcinoma-Derived Extracellular Vesicle MicroRNAs Induce a Neoplastic Phenotype in Gastric Organoids.

Author information

1
Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China; Department of Gastroenterology, the First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China; Department of Medicine (GI Division), the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; Department of Oncology, the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
2
Department of Medicine (GI Division), the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; Department of Oncology, the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; Departments of Surgical Oncology, the First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
3
Department of Thoracic Surgery, Shandong University Qilu Hospital, Jinan, Shandong, PR China.
4
Department of Medicine (GI Division), the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; Department of Oncology, the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
5
Department of Biology, Goucher College, Baltimore, MD, USA.
6
Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
7
Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
8
Department of Medicine (GI Division), the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; Department of Oncology, the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; Departments of Pathology, the First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
9
Department of Medicine (GI Division), the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; Department of Oncology, the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; Departments of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
10
Department of Gastroenterology, the First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China. Electronic address: hesx123@126.com.
11
Department of Medicine (GI Division), the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; Department of Oncology, the Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. Electronic address: smeltzer@jhmi.edu.

Abstract

There have been no reports describing the effects of cancer cell-derived extracellular vesicles (EVs) on three-dimensional organoids. In this study, we delineated the proneoplastic effects of esophageal adenocarcinoma (EAC)-derived EVs on gastric organoids (gastroids) and elucidated molecular mechanisms underlying these effects. EVs were identified using PKH-67 staining. Morphologic changes, Ki-67 immunochemistry, cell viability, growth rates, and expression levels of miR-25 and miR-210, as well as of their target mRNAs, were determined in gastroids co-cultured with EAC-derived extracellular vesicles (c-EVs). C-EVs were efficiently taken up by gastroids. Notably, c-EV-treated gastroids were more crowded, compact, and multilayered and contained smaller lumens than did those cultured in organoid medium alone or in EAC-conditioned medium that had been depleted of EVs. Moreover, c-EV-treated gastroids manifested increased proliferation and cellular viability relative to medium-only or EV-depleted controls. Expression levels of miR-25 and miR-210 were significantly higher, and those of PTEN and AIFM3 significantly lower, in c-EV-treated versus medium-only or EV-depleted control groups. Inhibitors of miR-25 and miR-210 reversed the increased cell proliferation induced by c-exosomes in co-cultured gastroids by lowering miR-25 and miR-210 levels. In conclusion, we have constructed a novel model system featuring the co-culture of c-EVs with three-dimensional gastroids. Using this model, we discovered that cancer-derived EVs induce a neoplastic phenotype in gastroids. These changes are due, at least in part, to EV transfer of miR-25 and miR-210.

PMID:
28968550
PMCID:
PMC5633352
DOI:
10.1016/j.neo.2017.06.007
[Indexed for MEDLINE]
Free PMC Article

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