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

Jianmei Gu,Xu Zhang,Yunyan Shi,Li Shen,Yongmin Yan,Wenrong Xu,Chonghui Zhao,Ling Huang,Hui Qian,Fei Mao,Wei Zhu,Rajeev Samant

doi:10.1371/journal.pone.0052465

Jianmei Gu, Xu Zhang + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0052465

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Abstract

BackgroundMesenchymal 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 FindingsWe 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/SignificanceOur 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.

Highlights

Tumor cells start to mold their microenvironment at early phase of the malignant progression [1]
Our data indicate that: (1) gastric cancer cell derived exosomes are internalized by human umbilical cord-derived MSCs (hucMSCs); (2) gastric cancer cell derived exosomes trigger hucMSCs differentiation to carcinoma-associated fibroblasts (CAFs) and (3) TGF-b/Smad pathway mediates the transition of hucMSCs to CAFs
Our findings suggest that TGF-b in tumor exosomes may interact with the TGF-b R1 on hucMSCs, resulting in the activation of Smad pathway in hucMSCs and the subsequent differentiation of hucMSCs to CAFs

Summary

Introduction

Tumor cells start to mold their microenvironment at early phase of the malignant progression [1]. Extensive reports have demonstrated the widespread interactions between tumor microenvironment and cancer cells, which are critical for tumorigenesis and tumor progression [2,3]. Tumor microenvironment is composed of diverse types of cells, including carcinoma-associated fibroblasts (CAFs), infiltrating immune cells, blood and lymphatic vascular networks, and mesenchymal stem cells (MSCs) [4,5]. CAFs are key determinants in the malignant progression of cancer growth, vascularization, and metastasis. Mesenchymal stem cells (MSCs) promote tumor growth by differentiating into carcinoma-associated fibroblasts (CAFs) and composing the tumor microenvironment. We aimed to investigate whether cancer cell-derived exosomes were involved in regulating the differentiation of human umbilical cord-derived MSCs (hucMSCs) to CAFs

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