Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells.

Olivier T. Giger,Ahlam Alqahtani,J. Dinesh Kumar,Mark Penfold,Robert J. Beynon,Timothy C. Wang,Andrea Varro,Chris Holmberg,Sandhir Kandola,Rosalind Jenkins,Graham J. Dockray,Laszlo Tiszlavicz,Peter Hegyi,Trevor T. Charvat,Islay Steele,David Peeney

doi:10.1371/journal.pone.0104877

Olivier T. Giger, Ahlam Alqahtani + Show 14 more

Open Access

https://doi.org/10.1371/journal.pone.0104877

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Journal: PloS one	Publication Date: Aug 15, 2014
Citations: 79	License type: CC BY 4.0

Affiliation: University of Liverpool, ChemoCentryx (United States)

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.

Highlights

The importance of the tumor microenvironment in determining cancer cell growth and spread is well recognised [1]
Myofibroblasts identified by a-SMA expression were found in greater numbers and exhibited disrupted morphology and architecture in esophageal squamous cell carcinoma (ESCC) compared with adjacent tissue (Fig S1 in File S2)
Using iTRAQ labeling followed by LC-MS/MS to identify potential cell signalling molecules secreted by cancer associated myofibroblasts (CAMs), we found increased chemerin abundance in CAM media compared with adjacent tissue myofibroblasts (ATMs) from all of four pairs of ESCC samples (Fig S4 in File S2; Table S3 in File S1)

Summary

Introduction

The importance of the tumor microenvironment in determining cancer cell growth and spread is well recognised [1]. In the case of the latter a growing body of evidence indicates that cancer-associated fibroblasts (CAFs), of which myofibroblasts are a prominent subtype, differ from their counterparts in normal tissue [3,4,5]. There is a growing appreciation that bone marrow derived mesenchymal stromal (stem) cells (MSCs) can influence cancer progression by migration to tumor sites where they may differentiate into a variety of cell types including myofibroblasts [6,7]; they may be useful as vehicles to provide targeted anticancer therapy [8]. There is a growing appreciation of the role of CAFs/myofibroblasts in ESCC in promoting cancer invasion and angiogenesis in general these remain poorly understood [12,13]

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