Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis.
BACKGROUND
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. Within the CXC group of chemokines, DARC binds the angiogenic CXC chemokines including IL-8 (CXCL8), GROalpha (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.


RESULTS
NSCLC 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.


CONCLUSIONS
The 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.
Addison
Christina L
CL
Departments of Medicine, Pathology, and Pediatrics, Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles CA, 90024-1922 USA. Christina.Addison@orcc.on.ca
Belperio
John A
JA
Burdick
Marie D
MD
Strieter
Robert M
RM
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000276:immunology* / Q000556:secondary; D016207:Cytokines / Q000378:metabolism; D004375:Duffy Blood-Group System / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C473745:ACKR1 protein, human; D016207:Cytokines; D004375:Duffy Blood-Group System; D016209:Interleukin-8; D011956:Receptors, Cell Surface