Soluble CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic adam protease activity

Objectives The chemokine CXCL16 is a transmembrane protein, which can be cleaved into a soluble form (sCXCL16) by ADAMs. CXCL16 and its receptor CXCR6 are reported to aid the anti-tumor immune response, but also have pro-metastatic properties. Their precise role seems to depend on tumor type. In the current study, we aimed to characterize the role of sCXCL16, CXCL16, and CXCR6 in ovarian cancer. Methods Immunohistochemistry was performed for CXCL16 and CXCR6 on tissue samples from 306 ovarian cancer patients. sCXCL16 levels were determined in 118 patients using ELISA. To assess ADAM effects on CXCL16 processing, cell line A2780 and primary ovarian cancer samples were treated with ADAM inhibitor TAPI-2. CXCL16 expression was evaluated by confocal microscopy and sCXCL16 was quantified in culture supernatants using ELISA. The effect of TAPI-2 on cell migration was assessed using scratch assays. Results sCXCL16 was an independent predictor of poor survival (Hazard Ratio 2.28, 95% confidence interval 1.29-4.02, p=0.005), whereas CXCL16 and CXCR6 did not correlate with survival. sCXCL16 was not associated with lymphocyte infiltration, nor with transmembrane CXCL16 expression. Therefore, high serum sCXCL16 may not be associated with CXCL16/CXCR6 signaling, but reflect its processing by ADAMs. Accordingly, in vitro ADAM inhibition decreased CXCL16 shedding and strongly reduced cell migration of A2780 and primary ovarian cancer cells. Conclusions High serum sCXCL16 is a prognostic marker for poor survival, possibly reflecting higher pro-metastatic ADAM activity. ADAM activity is difficult to quantify in vivo. Therefore, serum sCXCL16 levels may be a useful pseudomarker that identifies patients with more aggressive tumors.