title: The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers.
abstract: Clinical observations and mouse models have suggested that inflammation can be pro-tumorigenic. Since chemokines are critical in leukocyte trafficking, we hypothesized that chemokines play essential roles in inflammation-associated cancers. Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine. Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells. Expression levels of CXCL16 and CXCR6 on cancer cells correlated with poor prognostic features including high-stage and high-grade, and expression also correlated with post-inflammatory changes in the cancer stroma as revealed by loss of alpha-smooth muscle actin. Moreover, CXCL16 enhanced the growth of CXCR6-expressing cancer and primary CD4 T cells. We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation. Our study is the first to describe the expression of CXCL16/CXCR6 on both cancer cells and adjacent T cells in humans, and to demonstrate correlations between CXCL16 and CXCR6 vs. poor both prognostic features and reactive changes in cancer stoma. Taken together, our data suggest that CXCL16 and CXCR6 may mark cancers arising in an inflammatory milieu and mediate pro-tumorigenic effects of inflammation through direct effects on cancer cell growth and by inducing the migration and proliferation of tumor-associated leukocytes.
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. meravd@hadassah.org.il
authors.forename: Merav
authors.initials: M
authors.lastname: Darash-Yahana
authors.forename: John W
authors.initials: JW
authors.lastname: Gillespie
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Yun-Yun K
authors.initials: YY
authors.lastname: Chen
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Ilan
authors.initials: I
authors.lastname: Stein
authors.forename: Satya P
authors.initials: SP
authors.lastname: Singh
authors.forename: Roble B
authors.initials: RB
authors.lastname: Bedolla
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
authors.forename: Dean A
authors.initials: DA
authors.lastname: Troyer
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Farber
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications*; D008297:Male; D011471:Prostatic Neoplasms / Q000150:complications / Q000378:metabolism*; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000378:metabolism*; D051116:Receptors, Scavenger / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
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
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