title: TNFα-activated mesenchymal stromal cells promote breast cancer metastasis by recruiting CXCR2+neutrophils.
abstract: Mesenchymal stromal cells (MSCs) tend to infiltrate into tumors and form a major component of the tumor microenvironment. Our previous work demonstrated that tumor necrosis factor α (TNFα)-activated MSCs significantly promoted tumor growth. However, the role of TNFα-treated MSCs in tumor metastasis remains elusive. Employing a lung metastasis model of murine breast cancer, we found that TNFα-activated MSCs strikingly enhanced tumor metastasis compared with normal MSCs. We analyzed the chemokine profiles and found that the expression of CCL5, CCR2 and CXCR2 ligands were enhanced in TNFα-activated MSCs. Using genetic or pharmacological strategies to inhibit CCL5 or CCR2, we demonstrated that CCL5 and CCR2 ligands were indispensable in supporting TNFα-activated MSCs to promote tumor metastasis. Analysis of immune cells revealed that CXCR2 ligands (CXCL1, CXCL 2 and CXCL5) expressed by TNFα-activated MSCs efficiently recruited CXCR2+neutrophils into tumor. These neutrophils were responsible for the pro-metastatic effect of MSCs since inhibition of this chemotaxis abolished increased neutrophil recruitment and tumor metastasis. The interaction between neutrophils and tumor cells resulted in markedly elevated metastasis-related genes by tumor cells, including CXCR4, CXCR7, MMP12, MMP13, IL-6 and TGFβ. Importantly, in IL8highhuman breast cancer samples, we also observed similar alterations of gene expression. Collectively, our findings demonstrate that TNFα-activated MSCs promote tumor metastasis via CXCR2+neutrophil recruitment.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: P F
authors.initials: PF
authors.lastname: Yu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Y
authors.identifier: 0000-0001-5602-9871
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Han
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: L Y
authors.initials: LY
authors.lastname: Lin
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: W H
authors.initials: WH
authors.lastname: Sun
authors.affiliation: Child Health Institute of New Jersey, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Rabson
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.|Child Health Institute of New Jersey, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.|The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China.
authors.forename: Y F
authors.initials: YF
authors.lastname: Shi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D023063:Receptors, Interleukin-8B / Q000276:immunology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*
chemical_list: D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha