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Angiogenesis, Metastasis, and the Cellular Microenvironment

CXCL16 Functions as a Novel Chemotactic Factor for Prostate Cancer Cells In vitro

¹ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; ² Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry; ³ VA Medical Center and Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; ⁴ Wu Jieping Medical Foundation, Beijing, China; and ⁵ Laboratory for Clinical Biochemistry, Tianjin Chest Hospital, Tianjin, China

Requests for reprints: Jian Zhang, Department of Medicine, Room 2E110, Pittsburgh VA Healthcare System, Research and Development (151-U), University Drive, University of Pittsburgh, Pittsburgh, PA 15240. Phone: 412-527-8327; Fax: 412-688-6960. E-mail: zhangj2{at}upmc.edu

A variety of tumor cells produce chemokines that promote tumor cell proliferation and chemotaxis. We previously reported that CXCL16 production is increased in aggressive prostate cancer cells compared with the less aggressive tumor cells and benign cells as identified in a cytokine antibody array. The functional contribution of CXCL16 in prostate cancer development has not yet been evaluated. Accordingly, mRNA expression of CXCL16 and its receptor, CXCR6, were determined by real-time reverse transcription-PCR in various cancer cell lines, including prostate cancer and tissues obtained from localized and metastatic prostate cancer. Consistent with our finding on CXCL16 protein production by prostate cancer cells, aggressive prostate cancer C4-2B and PC3 cells, as well as bone and liver metastatic tissues, expressed higher levels of both CXCL16 and CXCR6 mRNA compared with the less aggressive prostate cancer LNCaP cells, nonneoplastic PrEC and RWPE-1 cells, and benign prostate tissues, respectively. Furthermore, CXCR6 and CXCL16 protein expressions were examined in tissue specimens by immunohistochemistry. Immunohistochemical examination of CXCR6 expression showed strong epithelial staining that correlated with Gleason score, whereas CXCL16 staining was not. Finally, we found that both interleukin-1β and tumor necrosis factor significantly induced CXCL16 production by prostate epithelial cells, thereby indicating that inflammatory cytokines may play a role in the CXCL16 induction. CXCL16 was found to promote prostate cancer cell migration and invasion in vitro. Therefore, we concluded that CXCL16 functions, through CXCR6, as a novel chemotactic factor for prostate cancer cells. (Mol Cancer Res 2008;6(4):546–54)