title: The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression.
abstract: Emerging evidence indicate that mesenchymal stem cells (MSCs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are essential component of the tumor microenvironment and are critically involved in cancer progression. Whether the phenotype and function of neutrophils is influenced by MSCs is not well understood. Herein, we investigated the interaction between neutrophils and gastric cancer-derived MSCs (GC-MSCs) and explored the biological role of this interaction. We found that GC-MSCs induced the chemotaxis of neutrophils and protected them from spontaneous apoptosis. Neutrophils were activated by the conditioned medium from GC-MSCs with increased expression of IL-8, TNFα, CCL2, and oncostatin M (OSM). GC-MSCs-primed neutrophils augmented the migration of gastric cancer cells in a cell contact-dependent manner but had minimal effect on gastric cancer cell proliferation. In addition, GC-MSCs-primed neutrophils prompted endothelial cells to form tube-like structure in vitro. We demonstrated that GC-MSCs stimulated the activation of STAT3 and ERK1/2 pathways in neutrophils, which was essential for the functions of activated neutrophils. We further revealed that GC-MSCs-derived IL-6 was responsible for the protection and activation of neutrophils. In turn, GC-MSCs-primed neutrophils induced the differentiation of normal MSCs into cancer-associated fibroblasts (CAFs). Collectively, our results suggest that GC-MSCs regulate the chemotaxis, survival, activation, and function of neutrophils in gastric cancer via an IL-6-STAT3-ERK1/2 signaling cascade. The reciprocal interaction between GC-MSCs and neutrophils presents a novel mechanism for the role of MSCs in remodeling cancer niche and provides a potential target for gastric cancer therapy.
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Central Laboratory, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Central Laboratory, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
authors.forename: X
authors.initials: X
authors.lastname: Yuan
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
authors.forename: F
authors.initials: F
authors.lastname: Mao
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhu
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
authors.forename: H
authors.initials: H
authors.lastname: Qian
authors.affiliation: 1] School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, China [2] The Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu, China.
authors.forename: W
authors.initials: W
authors.lastname: Xu
mesh_terms: D002633:Chemotaxis; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human