title: Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells.
abstract: Stromal cells such as myofibroblasts influence tumor progression. The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow-derived mesenchymal stromal cells (MSCs) which then colonize tumors. Using iTRAQ and LC-MS/MS we identified the adipokine, chemerin, as overexpressed in esophageal squamous cancer associated myofibroblasts (CAMs) compared with adjacent tissue myofibroblasts (ATMs). The chemerin receptor, ChemR23, is expressed by MSCs. Conditioned media (CM) from CAMs significantly increased MSC cell migration compared to ATM-CM; the action of CAM-CM was significantly reduced by chemerin-neutralising antibody, pretreatment of CAMs with chemerin siRNA, pretreatment of MSCs with ChemR23 siRNA, and by a ChemR23 receptor antagonist, CCX832. Stimulation of MSCs by chemerin increased phosphorylation of p42/44, p38 and JNK-II kinases and inhibitors of these kinases and PKC reversed chemerin-stimulated MSC migration. Chemerin stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor (MIF) that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations. In a xenograft model consisting of OE21 esophageal cancer cells and CAMs, homing of MSCs administered i.v. was inhibited by CCX832. Thus, chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression.
authors.affiliation: Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: J Dinesh
authors.initials: JD
authors.lastname: Kumar
authors.affiliation: Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Holmberg
authors.affiliation: Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Sandhir
authors.initials: S
authors.lastname: Kandola
authors.affiliation: Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Islay
authors.initials: I
authors.lastname: Steele
authors.affiliation: Department of Medicine and Surgery, University of Szeged, Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Hegyi
authors.affiliation: Department of Pathology, University of Szeged, Szeged, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Tiszlavicz
authors.affiliation: Department of Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Jenkins
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Beynon
authors.affiliation: Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Peeney
authors.affiliation: Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Olivier T
authors.initials: OT
authors.lastname: Giger
authors.affiliation: Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Ahlam
authors.initials: A
authors.lastname: Alqahtani
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, United States of America.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: ChemoCentryx, California, United States of America.
authors.forename: Trevor T
authors.initials: TT
authors.lastname: Charvat
authors.affiliation: ChemoCentryx, California, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Penfold
authors.affiliation: Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Dockray
authors.affiliation: Department of Cell and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism*; D002633:Chemotaxis; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011493:Protein Kinase C / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration
chemical_list: C102741:CMKLR1 protein, human; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; C478630:RARRES2 protein, human; D019707:Receptors, Chemokine; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human