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Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
1Correspondence: Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA. E-mail: alex.lentsch{at}uc.edu
ABSTRACT
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death among men in the United States. African American men have a 60% greater incidence of prostate cancer and a twofold higher mortality rate than Caucasian men. The Duffy antigen/receptor for chemokines (DARC) is a receptor expressed on erythrocytes and vascular endothelial cells that binds to and clears angiogenic chemokines. The DARC also functions as the erythrocyte receptor for invasion by malarial parasites. Approximately 70% of African Americans lack erythrocyte expression of the DARC as a genetic mechanism of protection against malaria infection. Given the importance of angiogenic chemokines in the development of tumor vascular networks and the chemokine binding properties of the DARC, the possibility that a lack of DARC expression on erythrocytes may represent an epigenetic factor that predisposes African American men to a greater incidence and mortality of prostate cancer should be considered.—Lentsch, A. B. The Duffy antigen/receptor for chemokines (DARC) and prostate cancer. A role as clear as black and white?
Key Words: angiogenesis • tumor • neovascularization
CANCER OF THE prostate is the leading cancer diagnosed in men and is the second leading cause of cancer-related death among men in the United States. As with many other forms of cancer, prostate cancer disproportionately affects the African American population. African American men have a 60% greater incidence of prostate cancer and a twofold higher mortality rate than Caucasian men (1)
. The causes of this increased susceptibility have not yet been identified. Whereas prostate carcinogenesis and neoplastic transformation may depend on a wide variety of genetic, environmental, and socioeconomic influences, growth of prostate tumors requires only an adequate supply of oxygen and nutrients to the tumor cells. This requirement is satisfied by the formation of a neovascular network within the tumor environment; a process called angiogenesis. Regulation of angiogenesis occurs via the local production of mediators that either promote (angiogenic) or inhibit (angiostatic) neovascularization. These mediators act primarily on microvascular endothelial cells by promoting/inhibiting endothelial cell chemotaxis, proliferation and tube formation. A wide variety of mediators possessing angiogenic or angiostatic properties have been identified, with >40 angiogenic and >30 angiostatic factors described in the literature. One class of mediators, a family of chemotactic cytokines called chemokines, contains multiple angiogenic and angiostatic factors.
Chemokines are a family of small peptide mediators that were originally described as the primary chemoattractant molecules responsible for the trafficking of leukocytes to sites of infection or inflammation. Even though these properties still define the nature of most chemokines, other important functions of chemokines have been discovered, including angiogenic and angiostatic activities (2)
. The nomenclature for chemokines is based on the configuration of a conserved amino-proximal cysteine-containing motif. Based on this system, there are currently four branches of the chemokine family: CXC, CC, CX3C, and C (where X is any amino acid) (3)
. Of relevance to tumor growth, chemokines of the CXC branch have been shown to exert either angiogenic or angiostatic activities depending on the presence or absence of the amino acid sequence Glu-Leu-Arg (ELR motif). The ELR motif, which is found in the amino terminus of all angiogenic CXC chemokines but in none of the angiostatic CXC chemokines, has been shown to be required for angiogenic activity by site-directed mutagenesis studies (4)
. Table 1
shows CXC chemokines with angiogenic or angiostatic properties.
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Angiogenic CXC chemokines have been implicated in the pathogenesis of prostate cancer. Immunohistochemical studies of human prostate tissues have shown that prostate tumors express abundant amounts of CXCL8 whereas normal prostate and benign prostatic hyperplasia tissues express very little, if any, CXCL8 (5)
. Other studies have shown that serum levels of CXCL8 are not increased in patients with benign prostatic hyperplasia, but in patients with prostate cancer, serum CXCL8 correlated with increasing stage of prostatic disease (6)
. These clinical findings are supported by in vitro studies of prostate cancer cell lines. Some prostate cancer cell lines endogenously produce high levels of angiogenic CXC chemokines, and stimulation with cytokines induces even greater production of these mediators (5
, 7)
. Furthermore, when prostate cancer cells were injected into SCID mice, tumor growth could be attenuated with blocking antibodies to CXCL1 or CXCL8 (7)
. Other studies demonstrated that prostate cancer cells engineered to overexpress CXCL8 were significantly more tumorigenic and metastatic than control cells (8)
. These data suggest that angiogenic CXC chemokines may be critically important for the growth and development of prostate tumors in humans.
The effects of angiogenic and angiostatic chemokines are mediated by specific receptors for these ligands. Chemokine receptors often recognize more than one chemokine, but they bind only chemokines within a single class (i.e., CC, CXC, etc.) (9)
. Thus, chemokine receptors are organized by chemokine subclass specificity: CC chemokine receptors bind CC chemokines, CXC chemokine receptors bind CXC chemokines, etc. There is one exception to this rule, the Duffy antigen/receptor for chemokines (DARC) (10)
. The DARC can bind members of both CC and CXC chemokine subclasses (11)
. Another interesting feature of the DARC is that it binds angiogenic (ELR+) CXC chemokines but not angiostatic (ELR-) CXC chemokines. Other than the DARC, however, ELR+ CXC chemokines bind only to CXC chemokine receptor 1 (CXCR1) or CXCR2, both of which are expressed on vascular endothelial cells (12
, 13)
. ELR- CXC chemokines bind to a variety of receptors, but the angiostatic CXC chemokines CXCL9 and CXCL10 bind to CXCR3. The receptor for the angiostatic CXC chemokine, CXCL4, has not been identified. Table 2
shows angiogenic and angiostatic CXC chemokines and the receptors to which they bind.
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The angiogenic effects of ELR+ CXC chemokines are mediated by CXCR2 and not CXCR1 (4)
. The angiostatic effects of the ELR- CXC chemokines are thought to be mediated by CXCR3. Although this premise has not been definitively proved, recent studies provide strong supportive evidence that CXCR3 is the receptor mediating the antiproliferative effects of CXCL9 and CXCL10 on endothelial cells in vitro (14)
. As mentioned above, the DARC is a promiscuous receptor that binds to chemokines of both CC and CXC classes, but only ELR+ CXC chemokines. Originally identified as an erythrocyte receptor, the DARC was subsequently proved to be identical to the Duffy blood group antigen (15
, 16)
, which is a binding protein for the malarial parasite Plasmodium vivax (17)
. The DARC has since been found to be expressed on vascular endothelial cells, as well as erythrocytes (18)
. More than 95% of Africans in endemic regions and 
70% of African Americans lack erythroid expression of the DARC as a natural selection against P. vivax infection (19)
. These individuals retain DARC expression on their vascular endothelium (20)
. Unlike other chemokine receptors, the DARC lacks a motif in the second intracellular loop that is associated with G-protein coupling (21)
. Thus, ligand binding by the DARC does not induce signal transduction. Mice lacking expression of the DARC on both erythrocytes and endothelial cells have been generated (22)
. Our initial characterization of these mice suggests that the DARC functions as a biological ‘sink’ for chemokines. These data have shown that erythrocytes from DARC+/+ mice have a strong binding profile for CXCL8 whereas erythrocytes from DARC-/- mice do not bind CXCL8 (22)
. Similarly, in a model of lipopolysaccharide-induced endotoxemia in which there is increased production of chemokines, we have shown that DARC knockout mice have an enhanced inflammatory response in multiple organs (22)
. These data suggest that the DARC serves as a regulator of these chemokine-mediated processes. The DARC also appears to have a regulatory role in angiogenesis. Transgenic mice overexpressing DARC on the vascular endothelium displayed a reduced angiogenic response to the angiogenic murine CXC chemokine MIP-2 in the corneal micropocket assay (23)
. Thus, consistent with our data in inflammatory models, it appears that the DARC functions to clear angiogenic CXC chemokines from the tissue microcirculation and thus may serve as a negative regulator of the angiogenic process.
This raises an interesting theory regarding the progression of prostate cancer in African American men. It is tempting to suggest that in individuals that express the DARC on their erythrocytes that the DARC functions as a sponge for these angiogenic chemokines; as blood flows through the tumor microcirculation, the DARC on erythrocytes binds and removes angiogenic chemokines. The lack of erythrocyte expression of the DARC, as occurs in 70% of the African American population, may remove a regulatory mechanism that serves to restrict prostate tumor growth. Thus, lack of DARC expression on erythrocytes may represent an epigenetic factor that predisposes African American men to a greater incidence and mortality of prostate cancer. In this scenario, individuals lacking erythrocyte expression of the DARC would have higher intra-tumor concentrations of angiogenic chemokines, such as CXCL1 and CXCL8, which could contribute to increased tumor angiogenesis and growth. Is it coincidence that the majority of the African American population lacks erythroid expression of the DARC and that this same population is more than twice as likely to succumb to prostate cancer than Caucasian men? This question may soon be answered with the combined use of genetic analysis and novel animal models of prostate cancer.
ACKNOWLEDGMENTS
This work was supported by a grant from the Department of Defense Prostate Cancer Research Program.
Received for publication February 5, 2002. Revision received March 6, 2002. REFERENCES
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  C. Vergara, Y. J. Tsai, A. V. Grant, N. Rafaels, L. Gao, T. Hand, M. Stockton, M. Campbell, D. Mercado, M. Faruque, et al. Gene Encoding Duffy Antigen/Receptor for Chemokines Is Associated with Asthma and IgE in Three Populations Am. J. Respir. Crit. Care Med., November 15, 2008; 178(10): 1017 - 1022. [Abstract] [Full Text] [PDF]
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