Gastric Cancer Exosomes Trigger Differentiation of Umbilical Cord Derived Mesenchymal Stem Cells to Carcinoma-Associated Fibroblasts through TGF-β/Smad Pathway

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Abstract

Background

Mesenchymal stem cells (MSCs) promote tumor growth by differentiating into carcinoma-associated fibroblasts (CAFs) and composing the tumor microenvironment. However, the mechanisms responsible for the transition of MSCs to CAFs are not well understood. Exosomes regulate cellular activities by mediating cell-cell communication. In this study, we aimed to investigate whether cancer cell-derived exosomes were involved in regulating the differentiation of human umbilical cord-derived MSCs (hucMSCs) to CAFs.

Methodology/Principal Findings

We first showed that gastric cancer cell-derived exosomes induced the expression of CAF markers in hucMSCs. We then demonstrated that gastric cancer cell-derived exosomes stimulated the phosphorylation of Smad-2 in hucMSCs. We further confirmed that TGF-β receptor 1 kinase inhibitor attenuated Smad-2 phosphorylation and CAF marker expression in hucMSCs after exposure to gastric cancer cell-derived exosomes.

Conclusion/Significance

Our results suggest that gastric cancer cells triggered the differentiation of hucMSCs to CAFs by exosomes-mediated TGF-β transfer and TGF-β/Smad pathway activation, which may represent a novel mechanism for MSCs to CAFs transition in cancer.

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Most cited references 23

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Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo.

Wei Zhu, Ling Huang, Yahong Li … (2012)

Mesenchymal stem cells (MSCs) can promote tumor growth in a mouse xenograft model, but the exact mechanism remains unclear. In this study, we investigated the effects of bone marrow MSC-derived exosomes (MSC-exosomes) on tumor growth in vitro and in vivo. Our results showed that MSC-exosomes promoted tumor growth in vivo. MSC-exosomes enhanced vascular endothelial growth factor (VEGF) expression in tumor cells by activating extracellular signal-regulated kinase1/2 (ERK1/2) pathway. Inhibition of ERK1/2 activation reserved the increase of VEGF level by MSC-exosomes. Our findings demonstrate a new mechanism through which MSC-exosome-mediated cell-cell interactions may contribute to tumor progression. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2.

Aled Clayton, J. Mitchell, Jacquelyn Court … (2007)

Exosomes are nanometer-sized vesicles, secreted by normal and neoplastic cells. The outcome following interaction between the cellular immune system and cancer-derived exosomes is not well understood. Interleukin-2 (IL-2) is a key factor supporting expansion and differentiation of CTL and natural killer (NK) cells but can also support regulatory T cells and their suppressive functions. Our study examined whether tumor-derived exosomes could modify lymphocyte IL-2 responses. Proliferation of healthy donor peripheral blood lymphocytes in response to IL-2 was inhibited by tumor exosomes. In unfractionated lymphocytes, this effect was seen in all cell subsets. Separating CD4(+) T cells, CD8(+) T cells, and NK cells revealed that CD8(+) T-cell proliferation was not inhibited in the absence of CD4(+) T cells and that NK cell proliferation was only slightly impaired. Other exosome effects included selective impairment of IL-2-mediated CD25 up-regulation, affecting all but the CD3(+)CD8(-) T-cell subset. IL-2-induced Foxp3 expression by CD4(+)CD25(+) cells was not inhibited by tumor exosomes, and the suppressive function of CD4(+)CD25(+) T cells was enhanced by exosomes. In contrast, exosomes directly inhibited NK cell killing function in a T-cell-independent manner. Analysis of tumor exosomes revealed membrane-associated transforming growth factor beta(1) (TGFbeta(1)), which contributed to the antiproliferative effects, shown by using neutralizing TGFbeta(1)-specific antibody. The data show an exosome-mediated mechanism of skewing IL-2 responsiveness in favor of regulatory T cells and away from cytotoxic cells. This coordinated "double hit" to cellular immunity strongly implicates the role of exosomes in tumor immune evasion.

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Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function.

Cunren Liu, Shaohua Yu, Kurt Zinn … (2006)

Many tumor cells shed specialized membrane vesicles known as exosomes. In this study, we show that pretreatment of mice with exosomes produced by TS/A or 4T.1 murine mammary tumor cells resulted in accelerated growth of implanted tumor cells in both syngeneic BALB/c mice and nude mice. As implanted TS/A tumor cells grew more rapidly in mice that had been depleted of NK cells, we analyzed the effects of the tumor-derived exosomes on NK cells. The tumor-derived exosomes inhibit NK cell cytotoxic activity ex vivo and in vitro as demonstrated by chromium release assays. The treatment of mice with TS/A tumor exosomes also led to a reduction in the percentages of NK cells, as determined by FACS analysis, in the lungs and spleens. Key features of NK cell activity were inhibited, including release of perforin but not granzyme B, as well as the expression of cyclin D3 and activation of the Jak3-mediated pathways. Human tumor cell lines also were found to produce exosomes that were capable of inhibiting IL-2-stimulated NK cell proliferation. Exosomes produced by dendritic cells or B cells did not. The presentation of tumor Ags by exosomes is under consideration as a cancer vaccine strategy; however, we found that pretreatment of mice with tumor exosomes blunted the protective effect of syngeneic dendritic cells pulsed ex vivo with tumor exosomes. We propose that tumor exosomes contribute to the growth of tumors by blocking IL-2-mediated activation of NK cells and their cytotoxic response to tumor cells.

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Author and article information

Contributors

Rajeev Samant: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 20 December 2012

Volume: 7

Issue: 12

Electronic Location Identifier: e52465

Affiliations

[1 ]School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China

[2 ]Department of Clinical Laboratory Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China

University of Alabama at Birmingham, United States of America

Author notes

* E-mail: icls@ 123456ujs.edu.cn (WX); lstmmmlst@ 123456163.com (HQ)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: WX JG. Performed the experiments: JG. Analyzed the data: JG WZ LH. Contributed reagents/materials/analysis tools: HQ LS YY FM CZ YS. Wrote the paper: JG XZ.

Article

Publisher ID: PONE-D-12-21446

DOI: 10.1371/journal.pone.0052465

PMC ID: 3527492

PubMed ID: 23285052

SO-VID: dd67d715-a5f2-4f3c-9450-ed5aeb218e6d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 30 June 2012

Date accepted : 13 November 2012

Page count

Pages: 8

Funding

This work was supported by the Major Research Plan of the National Natural Science Foundation of China (Grant no. 91129718), the National Natural Science Foundation of China (Grant no. 81071421, 31140063), Jiangsu Province’s Scientific and Technological Supporting Program (Grant no. BE2010703), 333 Project of Jiangsu Province (Grant no. 2009055) and the Sci-Tech Innovation Team and Talents of Jiangsu University (Grant no. 2008-018-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Gastric Cancer Exosomes Trigger Differentiation of Umbilical Cord Derived Mesenchymal Stem Cells to Carcinoma-Associated Fibroblasts through TGF-β/Smad Pathway

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Abstract

Background

Methodology/Principal Findings

Conclusion/Significance

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PLOS Climate

Most cited references 23

Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo.

Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2.

Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function.

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