title: Elevated serum CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic ADAM protease activity.
abstract: 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.
authors: 1] Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands [2] Department of Surgery, Translational Surgical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: M J M
authors: MJ
authors: Gooden
authors: Department of Surgery, Translational Surgical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: V R
authors: VR
authors: Wiersma
authors: 1] Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands [2] Department of Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: A
authors: A
authors: Boerma
authors: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: N
authors: N
authors: Leffers
authors: Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: H M
authors: HM
authors: Boezen
authors: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: K A
authors: KA
authors: ten Hoor
authors: Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: H
authors: H
authors: Hollema
authors: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: A M E
authors: AM
authors: Walenkamp
authors: Department of Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: T
authors: T
authors: Daemen
authors: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: H W
authors: HW
authors: Nijman
authors: Department of Surgery, Translational Surgical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: E
authors: E
authors: Bremer
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000097:blood*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000097:blood* / Q000201:enzymology / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000097:blood; D051116:Receptors, Scavenger / Q000096:biosynthesis / Q000097:blood*; D011991:Receptors, Virus / Q000096:biosynthesis / Q000097:blood; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: C423727:CXCL16 protein, human; C106330:CXCR6 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D008565:Membrane Proteins; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger; D011991:Receptors, Virus; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human