Expression of CCL5 (RANTES) and its receptors in prostate cancer

4696 Inflammation has long been considered a contributing factor in the development and advancement of cancer. Expression of the prototypic inflammatory chemokine CCL5 (RANTES) by tumor cells is thought to correlate with the progression of several cancers, through the recruitment of inflammatory leukocytes. Furthermore, CCL5 was shown to induce breast cancer cell migration, mediated by the receptor CCR5. A CCR5 antagonist was also demonstrated to inhibit experimental breast tumor growth. Recently, CCL5 and CCR5 mRNA expression was reported in prostate cancer (PCa) tissues. In this study, we characterized CCL5 and CCR5 expression in cultures of PCa cells and explored possible functions of CCL5 in PCa progression. CCL5 mRNA and protein expression were found in human PCa cell lines (PC-3; DU-145; LNCaP) and primary prostate adenocarcioma cells by quantitative RT-PCR and ELISA. CCL5 was detected in human PCa tissues by immunohistochemical staining. CCR5 expression was demonstrated on the cell-surface of PCa cells by flow cytometry, as well as in large intracellular pools within the cells. To determine whether PCa cell-derived CCL5 may affect inflammatory cell infiltration, monocyte chemotaxis assays were performed. Conditioned media from PCa cells induced THP-1 monocyte chemotaxis, which was inhibited by anti-CCL5 antibodies. We further studied whether CCL5 directly affects PCa cells. We found that incubation with CCL5 (10-100 ng/ml) induced PCa cell proliferation, and that the CCR5 antagonist TAK-779 inhibited CCL5-induced proliferation. CCL5 was also found to stimulate PCa cell invasion through basement membrane gels, and TAK-779 inhibited CCL5-induced cell invasion. In light of growing evidence that inflammation influences the pathogenesis of PCa, these results suggest that chemokines, such as CCL5, expressed by prostate cells may affect the degree of local inflammatory infiltrates, as well as act directly on the growth and survival of PCa cells. Chemokine receptor antagonists may thus block both paracrine and autocrine mechanisms of PCa progression.