Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells
Kumar, Jothi Dinesh; Holmberg, Christopher; Kandola, Sandhir; Steele, Islay; Hegyi, Peter; Tiszlavicz, Lazlo; Jenkins, Roz; Beynon, Rob; Peeney, David; Giger, Olivier; Alqahtani, Ahlam; Wang, Timothy C; Charvat, Trevor T; Penfold, Mark; Dockray, Graham; Varro, Andrea
Stromal cells such as myofibroblasts influence tumor progression. The mechanisms 45 are unclear but may involve effects on both tumor cells and recruitment of bone 46 marrow-derived mesenchymal stromal cells (MSCs) which then colonize tumors. 47 Using iTRAQ and LC-MS/MS we identified the adipokine, chemerin, as 48 overexpressed in esophageal squamous cancer associated myofibroblasts (CAMs) 49 compared with adjacent tissue myofibroblasts (ATMs). The chemerin receptor, 50 ChemR23, is expressed by MSCs. Conditioned media (CM) from CAMs significantly 51 increased MSC cell migration compared to ATM-CM; the action of CAM-CM was 52 significantly reduced by chemerin-neutralising antibody, pretreatment of CAMs with 53 chemerin siRNA, pretreatment of MSCs with ChemR23 siRNA, and by a ChemR23 54 receptor antagonist, CCX832. Stimulation of MSCs by chemerin increased 55 phosphorylation of p42/44, p38 and JNK-II kinases and inhibitors of these kinases 56 and PKC reversed chemerin-stimulated MSC migration. Chemerin stimulation of 57 MSCs also induced expression and secretion of macrophage inhibitory factor (MIF) 58 that tended to restrict migratory responses to low concentrations of chemerin but not 59 higher concentrations. In a xenograft model consisting of OE21 esophageal cancer 60 cells and CAMs, homing of MSCs administered i.v. was inhibited by CCX832. Thus, 61 chemerin secreted from esophageal cancer myofibroblasts is a potential 62 chemoattractant for MSCs and its inhibition may delay tumor progression.