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

Xiquan Ke, Rong Yan, Zhenguo Sun, Yulan Cheng, Amy Meltzer, Nonghua Lu, Xu Shu, Zhe Wang, Binbin Huang, Xi Liu, Zhixiong Wang, Jee Hoon Song, Christopher K. Ng, Sariat Ibrahim, John M. Abraham, Eun Shin, Shuixiang He, Stephen Meltzer

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)941-949
Number of pages9
JournalNeoplasia (United States)
Volume19
Issue number11
DOIs
StatePublished - Nov 1 2017

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Organoids
MicroRNAs
Stomach
Phenotype
Adenocarcinoma
Extracellular Vesicles
Cell Proliferation
Exosomes
Immunochemistry
Conditioned Culture Medium
Coculture Techniques

ASJC Scopus subject areas

  • Cancer Research

Cite this

Esophageal Adenocarcinoma–Derived Extracellular Vesicle MicroRNAs Induce a Neoplastic Phenotype in Gastric Organoids. / Ke, Xiquan; Yan, Rong; Sun, Zhenguo; Cheng, Yulan; Meltzer, Amy; Lu, Nonghua; Shu, Xu; Wang, Zhe; Huang, Binbin; Liu, Xi; Wang, Zhixiong; Song, Jee Hoon; Ng, Christopher K.; Ibrahim, Sariat; Abraham, John M.; Shin, Eun; He, Shuixiang; Meltzer, Stephen.

In: Neoplasia (United States), Vol. 19, No. 11, 01.11.2017, p. 941-949.

Research output: Contribution to journalArticle

Ke, X, Yan, R, Sun, Z, Cheng, Y, Meltzer, A, Lu, N, Shu, X, Wang, Z, Huang, B, Liu, X, Wang, Z, Song, JH, Ng, CK, Ibrahim, S, Abraham, JM, Shin, E, He, S & Meltzer, S 2017, 'Esophageal Adenocarcinoma–Derived Extracellular Vesicle MicroRNAs Induce a Neoplastic Phenotype in Gastric Organoids', Neoplasia (United States), vol. 19, no. 11, pp. 941-949. https://doi.org/10.1016/j.neo.2017.06.007
Ke, Xiquan ; Yan, Rong ; Sun, Zhenguo ; Cheng, Yulan ; Meltzer, Amy ; Lu, Nonghua ; Shu, Xu ; Wang, Zhe ; Huang, Binbin ; Liu, Xi ; Wang, Zhixiong ; Song, Jee Hoon ; Ng, Christopher K. ; Ibrahim, Sariat ; Abraham, John M. ; Shin, Eun ; He, Shuixiang ; Meltzer, Stephen. / Esophageal Adenocarcinoma–Derived Extracellular Vesicle MicroRNAs Induce a Neoplastic Phenotype in Gastric Organoids. In: Neoplasia (United States). 2017 ; Vol. 19, No. 11. pp. 941-949.
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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.",
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AU - Ke, Xiquan

AU - Yan, Rong

AU - Sun, Zhenguo

AU - Cheng, Yulan

AU - Meltzer, Amy

AU - Lu, Nonghua

AU - Shu, Xu

AU - Wang, Zhe

AU - Huang, Binbin

AU - Liu, Xi

AU - Wang, Zhixiong

AU - Song, Jee Hoon

AU - Ng, Christopher K.

AU - Ibrahim, Sariat

AU - Abraham, John M.

AU - Shin, Eun

AU - He, Shuixiang

AU - Meltzer, Stephen

PY - 2017/11/1

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N2 - 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.

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