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ABSTRACT: Angiogenic and angiostatic CXC chemokines mediate their effects via the receptors, CXCR2 and CXCR3, respectively. The current study sought to determine whether the presence of these receptors alters prostate tumor growth.
Endothelial cell chemotaxis of prostate cell-derived products was determined in vitro. Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice was bred with CXCR2- or CXCR3-knockout mice to determine the effects of these genes on prostate tumor growth.
Normal prostate epithelial cells release CXCR3 ligands that limit endothelial cell chemotaxis. Prostate cancer cells release CXCR2 ligands that stimulated endothelial cell chemotaxis. Tumors in TRAMP/CXCR2(-/-) mice were significantly smaller than those in TRAMP/CXCR2(+/+) mice and had reduced angiogenesis. In contrast, tumors in TRAMP/CXCR3(-/-) mice were palpable much earlier than TRAMP/CXCR3(+/+) mice and had greatly increased angiogenesis.
The data suggest that signaling through CXCR2 and CXCR3 represents important counter-regulatory mechanisms that control the growth of prostate tumors.
The Prostate 01/2007; 66(16):1721-8. · 3.48 Impact Factor
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ABSTRACT: The Duffy antigen/receptor for chemokines (DARC) is a promiscuous chemokine receptor that binds to members of the CXC chemokine family possessing angiogenic properties. The DARC is expressed on erythrocytes and endothelial cells and is required for Plasmodium vivax infection of erythrocytes. Approximately 70% of African-Americans lack erythrocyte expression of the DARC as a genetic mechanism of protection against malaria infection. African-American men have a 60% greater incidence of prostate cancer and a 2-fold higher mortality rate than Caucasian men. Using a transgenic model of prostate cancer with DARC-deficient mice, we tested the hypothesis that lack of DARC expression on erythrocytes contributes to enhanced prostate tumor growth. In vitro, erythrocytes from wild-type mice but not DARC-deficient mice cleared angiogenic chemokines produced by prostate cancer cells and reduced endothelial cell chemotaxis. In vivo, tumors from DARC-deficient mice had higher intra-tumor concentrations of angiogenic chemokines, increased tumor vessel density, and greatly augmented prostate tumor growth. The data suggest that the DARC functions to clear angiogenic CXC chemokines from the prostate tumor microcirculation and that the lack of erythroid DARC, as occurs in the majority of African-Americans, may be a contributing factor to the increased mortality to prostate cancer in this population.
The FASEB Journal 02/2006; 20(1):59-64. · 5.71 Impact Factor
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ABSTRACT: The CXC chemokine family includes members that possess angiogenic and angiostatic properties. Angiogenic CXC chemokines are produced by prostate cancer cells and contribute to prostate tumor growth. Production of angiostatic CXC chemokines by prostatic cells has not been previously studied. Here we show that normal prostate epithelial (PZ-HPV-7) cells produce low amounts of angiogenic CXC chemokines, whereas prostate cancer cells from primary (CA-HPV-10) and metastatic (PC-3) tumors produce progressively greater amounts. These effects were caused by progressive increases in activation of the transcription factor nuclear factor-kappa B in prostate cancer cells. Conversely, PZ-HPV-7 cells produced relatively high levels of angiostatic CXC chemokines, whereas CA-HPV-10 and PC-3 cells produced stepwise lower amounts. These effects were dependent on reduced activation of signal transduction and activator of transcription 1 (STAT1) in prostate cancer cells. These data suggest that there is progressive dysregulation of nuclear factor-kappa B and STAT1 in prostate cancer cells that leads to proangiogenic production of CXC chemokines.
AJP Cell Physiology 05/2004; 286(4):C840-7. · 3.54 Impact Factor
