Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis.

Christina L Addison,Marie D Burdick,Robert M Strieter,John A Belperio

doi:10.1186/1471-2407-4-28

Abstract

BackgroundThe Duffy antigen receptor for chemokines (DARC) is known to be a promiscuous chemokine receptor that binds a variety of CXC and CC chemokines in the absence of any detectable signal transduction events. Within the CXC group of chemokines, DARC binds the angiogenic CXC chemokines including IL-8 (CXCL8), GROα (CXCL1) and ENA-78 (CXCL5), all of which have previously been shown to be important in non-small cell lung carcinoma (NSCLC) tumor growth. We hypothesized that overexpression of DARC by a NSCLC tumor cell line would result in the binding of the angiogenic ELR+ CXC chemokines by the tumor cells themselves, and thus interfere with the stimulation of endothelial cells and induction of angiogenesis by the tumor cell-derived angiogenic chemokines.ResultsNSCLC tumor cells that constitutively expressed DARC were generated and their growth characteristics were compared to control transfected cells in vitro and in vivo in SCID animals. We found that tumors derived from DARC-expressing cells were significantly larger in size than tumors derived from control-transfected cells. However, upon histological examination we found that DARC-expressing tumors had significantly more necrosis and decreased tumor cellularity, as compared to control tumors. Expression of DARC by NSCLC cells was also associated with a decrease in tumor-associated vasculature and a reduction in metastatic potential.ConclusionsThe expression of DARC in the context of NSCLC tumors may act as a chemokine decoy receptor and interferes with normal tumor growth and chemokine-induced tumor neovascularization.

Highlights

The Duffy antigen receptor for chemokines (DARC) is known to be a promiscuous chemokine receptor that binds a variety of CXC and CC chemokines in the absence of any detectable signal transduction events
We detected DARC-specific message in both the DARC1A6 and DARC2F5 clones, no corresponding band was detected in the pTARGET empty vector control transfected A549 cell clone by northern blot analysis (Fig. 1)
It would appear that only a percentage of transfected cells express DARC at the surface of the cell, this is in agreement with the fact that these cells make IL-8 and ENA-78, it is likely that DARC is binding these chemokines in the endoplasmic

Summary

Introduction

The Duffy antigen receptor for chemokines (DARC) is known to be a promiscuous chemokine receptor that binds a variety of CXC and CC chemokines in the absence of any detectable signal transduction events. Expression of DARC in vivo is not limited to the red blood cell, and DARC expression has been detected in endothelial cells of the kidney, spleen and brain and in large vessel and post-capillary venules [1,2]. It has been detected in epithelial cells lining the ducts of the kidney, in pulmonary alveoli [8], and in a subset of neurons [9]. The expression of DARC by cells other than red blood cells suggests that its presence on these cells may be important in modifying the biological behavior of specific chemokines

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