Elevated serum CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic ADAM protease activity

• Published in: British journal of cancer Vol. 110; no. 6; pp. 1535 - 1544
• Main Authors: Gooden, M J M, Wiersma, V R, Boerma, A, Leffers, N, Boezen, H M, ten Hoor, K A, Hollema, H, Walenkamp, A M E, Daemen, T, Nijman, H W, Bremer, E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.03.2014; Nature Publishing Group
• Subjects: 692/53/2422; 692/699/67/1517/1709; 692/699/67/322; ADAM Proteins - metabolism; ADAM10 Protein; ADAM17 Protein; Amyloid Precursor Protein Secretases - metabolism; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chemokine CXCL16; Chemokines, CXC - biosynthesis; Chemokines, CXC - blood; Drug Resistance; Epidemiology; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Medical sciences; Membrane Proteins - metabolism; Molecular Diagnostics; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Oncology; Ovarian cancer; Ovarian Neoplasms - blood; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - pathology; Prognosis; Prospective Studies; Receptors, Chemokine - biosynthesis; Receptors, Chemokine - blood; Receptors, CXCR6; Receptors, Scavenger - biosynthesis; Receptors, Scavenger - blood; Receptors, Virus - biosynthesis; Receptors, Virus - blood; Survival Analysis; Tissue Array Analysis; Tumors; CXCR6; ovarian cancer; prognosis; ADAMs; CXCL16; Prognosis; Enzyme; Ovary cancer; Prediction; Malignant tumor; Metastasis; Survival; Biological activity; Female genital diseases; Ovarian diseases; Peptidases; Cancerology; A disintegrin and metalloproteinases; Hydrolases; Advanced stage; Serum; Predictive factor; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.55

Background: In certain cancers, expression of CXCL16 and its receptor CXCR6 associate with lymphocyte infiltration, possibly aiding anti-tumour immune response. In other cancers, CXCL16 and CXCR6 associate with pro-metastatic activity. In the current study, we aimed to characterise the role of CXCL16, sCXCL16, and CXCR6 in ovarian cancer (OC). Methods: CXCL16/CXCR6 expression was analysed on tissue microarray containing 306 OC patient samples. Pre-treatment serum sCXCL16 was determined in 118 patients using ELISA. In vitro , (primary) OC cells were treated with an ADAM-10/ADAM-17 inhibitor (TAPI-2) and an ADAM-10-specific inhibitor (GI254023x), whereupon CXCL16 levels were evaluated on the cell membrane (immunofluorescent analysis, western blots) and in culture supernatants (ELISA). In addition, cell migration was assessed using scratch assays. Results: sCXCL16 independently predicted for poor survival (hazard ratio=2.28, 95% confidence interval=1.29–4.02, P =0.005), whereas neither CXCL16 nor CXCR6 expression correlated with survival. Further, CXCL16/CXCR6 expression and serum sCXCL16 levels did not associate with lymphocyte infiltration. In vitro inhibition of both ADAM-17 and ADAM-10, but especially the latter, decreased CXCL16 membrane shedding and strongly reduced cell migration of A2780 and cultured primary OC-derived malignant cells. Conclusions: High serum sCXCL16 is a prognostic marker for poor survival of OC patients, possibly reflecting ADAM-10 and ADAM-17 pro-metastatic activity. Therefore, serum sCXCL16 levels may be a pseudomarker that identifies patients with highly metastatic tumours.