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CXCL16 is a recently discovered chemokine that is the only known ligand for the receptor CXCR6. To date, the expression of CXCL16 in cancer has not been described. A preliminary screen for chemokines in prostate cancer cell lines suggested significant expression of CXCL16. Immunohistochemical analysis of CXCL16 on prostate tissue specimens showed no expression in normal prostate tissue, but prominent expression in chronic prostatitis, pre-neoplastic lesions and in primary prostate cancer cases in which the malignant cells were surrounded by reactive stroma. Consistent with these findings, the inflammatory cytokines TNF-α and IFN-γ were found to induce the secretion of CXCL16 from both normal prostate epithelial cells and prostate tumor cell lines. The specificity of the anti-CXCL16 staining was shown by specific blocking using the chemokine domain of CXCL16 and by correlating CXCL16 staining of cell lines with levels of CXCL16 mRNA using real time RT-PCR, levels of surface CXCL16 using flow cytometry, and levels of secreted CXCL16 using ELISA. We further studied expression of CXCL16 on tissue microarrays and tissue sections from cancer patients in 603 cases of cancer including 12 tumor types. Greater than 50% of prostate, liver, colon, breast, ovary, and brain cancer cases showed high-level staining for CXCL16, while low or no staining was found in the majority of melanomas, lymphomas, or lung, head and neck, renal cell and thyroid cancers. Most of the cancer types that were found to express high levels of CXCL16 are known to arise in the context of inflammation. We extended our studies of CXCL16 and CXCR6 using two mouse models of inflammation-associated liver cancer that were previously described (Pikarsky et al., Nature 2004, 431:461-6; Maeda et al., Cell 2005, 121:977-990). Both CXCL16 and CXCR6 were up-regulated in livers that gave rise to inflammation-associated tumors as compared with the non-inflamed livers. The fold up-regulation of CXCL16, in involved livers, was similar to that of other inflammation-associated chemokines. We suggest that expression and secretion of CXCL16 from pre-malignant cells may lead to CXCR6-mediated recruitment and survival of inflammatory cells. Cytokines such as TNF-α and IFN-γ that are secreted by inflammatory cells in the tumor site may in turn lead to up regulation of CXCL16, creating a positive feedback loop that would enhance of the growth and survival of inflammation-associated cancers.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]