title: Prognostic impact of CXCL16 and CXCR6 in non-small cell lung cancer: combined high CXCL16 expression in tumor stroma and cancer cells yields improved survival.
abstract: BACKGROUND
  The chemokine CXCL16 and its receptor CXCR6 are expressed by a variety of immune cells and have been shown to influence angiogenesis. The expression of CXCR6 and CXCL16 has been examined in numerous human cancers; however no studies have yet investigated their influence on prognosis in non-small cell lung cancer (NSCLC). We aimed to explore their prognostic significance in NSCLC, in addition to examining associations with previously investigated markers.
  
  
  METHODS
  Resected tumor tissue from 335 consecutive unselected stage I-IIIA NSCLC patients (1990-2005) were collected. Immunohistochemistry was used to evaluate the expression of CXCR6 and CXCL16 on tissue microarrays. In vitro, NSCLC cells (NCI-H460, A549 cells) were transfected with CXCL16 siRNA to examine effects on proliferation.
  
  
  RESULTS
  In univariate analysis, ↑ stromal cell CXCL16 expression was a significant positive prognostic factor (P = 0.016). CXCR6 was expressed in cancer cells, but did not show any prognostic impact. In the multivariate analysis, combined ↑cancer, and ↑stromal cell CXCL16 expression was an independent positive prognostic factor when compared to ↓stromal and ↓cancer cell expression (HR: 0.42; 95 % CI: 0.20-0.88; P = 0.022). Knockdown of CXCL16 by siRNA resulted in accelerated proliferation of NSCLC cell lines.
  
  
  CONCLUSIONS
  We have shown that combined ↑cancer and ↑stromal cell CXCL16 expression is an independent positive prognostic factor in NSCLC. Further studies are warranted to elucidate the biological mechanism underlying this finding.
authors.affiliation: Department of Clinical Medicine, UiT The Arctic University of Norway, 9037, Tromso, Norway. sigurd.hald@uit.no.
authors.forename: Sigurd M
authors.initials: SM
authors.lastname: Hald
authors.affiliation: Department of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway.|Department of Pharmacy, UiT The Arctic University of Norway, Tromso, Norway.
authors.forename: Yury
authors.initials: Y
authors.lastname: Kiselev
authors.affiliation: Department of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway.|Department of Clinical Pathology, University Hospital of North Norway, Tromso, Norway.
authors.forename: Samer
authors.initials: S
authors.lastname: Al-Saad
authors.affiliation: Department of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway.|Department of Clinical Pathology, University Hospital of North Norway, Tromso, Norway.
authors.forename: Elin
authors.initials: E
authors.lastname: Richardsen
authors.affiliation: Department of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway.
authors.forename: Charles
authors.initials: C
authors.lastname: Johannessen
authors.affiliation: Department of Clinical Medicine, UiT The Arctic University of Norway, 9037, Tromso, Norway.
authors.forename: Marte
authors.initials: M
authors.lastname: Eilertsen
authors.affiliation: Department of Oncology, University Hospital of North Norway, Tromso, Norway.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Kilvaer
authors.affiliation: Department of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway.|Department of Pathology, Nordland Hospital, Bodo, Norway.
authors.forename: Khalid
authors.initials: K
authors.lastname: Al-Shibli
authors.affiliation: Department of Clinical Medicine, UiT The Arctic University of Norway, 9037, Tromso, Norway.|Department of Oncology, University Hospital of North Norway, Tromso, Norway.
authors.forename: Sigve
authors.initials: S
authors.lastname: Andersen
authors.affiliation: Department of Medical Biology, UiT The Arctic University of Norway, Tromso, Norway.|Department of Clinical Pathology, University Hospital of North Norway, Tromso, Norway.
authors.forename: Lill-Tove
authors.initials: LT
authors.lastname: Busund
authors.affiliation: Department of Clinical Medicine, UiT The Arctic University of Norway, 9037, Tromso, Norway.|Department of Oncology, University Hospital of North Norway, Tromso, Norway.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Bremnes
authors.affiliation: Department of Clinical Medicine, UiT The Arctic University of Norway, 9037, Tromso, Norway.|Department of Oncology, University Hospital of North Norway, Tromso, Norway.
authors.forename: Tom
authors.initials: T
authors.lastname: Donnem
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics; D051116:Receptors, Scavenger / Q000096:biosynthesis* / Q000235:genetics; D011991:Receptors, Virus / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C423727:CXCL16 protein, human; C106330:CXCR6 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger; D011991:Receptors, Virus