Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-β/Smad pathway

• Published in: PloS one Vol. 7; no. 12; p. e52465
• Main Authors: Gu, Jianmei, Qian, Hui, Shen, Li, Zhang, Xu, Zhu, Wei, Huang, Ling, Yan, Yongmin, Mao, Fei, Zhao, Chonghui, Shi, Yunyan, Xu, Wenrong
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.12.2012; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Antigens; Biology; Biomarkers, Tumor - metabolism; Bone marrow; Breast cancer; Cancer; Cell Differentiation; Cell interactions; Cell Line, Tumor; Cell Movement; Cell signaling; Dendritic cells; Differentiation; Endocytosis; Enzyme Activation; Enzyme inhibitors; Exosomes; Exosomes - metabolism; Exosomes - ultrastructure; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Gastric cancer; Gene expression; Humans; Laboratories; Medical research; Medicine; Mesenchymal stem cells; Mesenchymal Stromal Cells - enzymology; Mesenchymal Stromal Cells - pathology; Mesenchyme; Metastasis; p38 Mitogen-Activated Protein Kinases - metabolism; Penicillin; Phosphorylation; Science; Signal Transduction; Smad protein; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Stem cells; Stomach cancer; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Studies; Transforming Growth Factor beta - metabolism; Umbilical cord; Umbilical Cord - cytology; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0052465

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. 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. 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.