The chemokine receptor CXCR6 and its ligand CXCL16 are expressed in carcinomas and inhibit proliferation.
The chemokine receptor CXCR6 and its ligand CXCL16 are involved in inflammation. Thus far, they were known to be expressed mainly by T cells and macrophages, respectively. However, we detected both in all of 170 human primary mammary carcinomas and at similar levels in all 8 human mammary carcinoma cell lines tested by microarray analysis. Expression was confirmed by reverse transcription-PCR and for the cell lines also by fluorescence-activated cell sorting analysis. CXCR6 and CXCL16 were also detected in several mouse and human mammary, colon, and pancreatic carcinoma cell lines. CXCL16 is a transmembrane protein from which the soluble chemokine can be cleaved off. The transmembrane form is present on the surface of the carcinoma cells. Surprisingly, suppression of either CXCR6 or CXCL16 led to greatly enhanced proliferation in vitro as well as in vivo, indicating that their interaction inhibits proliferation. This notion was verified using inhibitory antibodies and by introduction of CXCL16 into a rare CXCL16-negative cell line. The effect was mediated by the G protein-coupled receptor CXCR6 because it was blocked by the G(i) protein inhibitor pertussis toxin. In contrast, the soluble CXCL16 chemokine enhanced proliferation, and this was also mediated by CXCR6 but not via G(i) protein. It is remarkable that both CXCR6 and CXCL16 are expressed by all mammary carcinomas because cells that lose either acquire a growth advantage and should be selected during tumor progression. This suggests an unknown important role in tumor formation. Proteases, possibly macrophage derived, might convert inhibitory transmembrane CXCL16 into the stimulatory chemokine.
Divisions of Cell Biology, Radiotherapy, Experimental Therapy, and Molecular Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Joost
J
Meijer
Janneke
J
Ogink
Bas
B
Kreike
Dimitry
D
Nuyten
Karin E
KE
de Visser
Ed
E
Roos
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008163:Luminescent Measurements; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D037342:Pertussis Toxin / Q000494:pharmacology; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D051116:Receptors, Scavenger / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*
C423727:CXCL16 protein, human; C106330:CXCR6 protein, human; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; C498926:Cxcl16 protein, mouse; C482906:Cxcr6 protein, mouse; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D051116:Receptors, Scavenger; D011991:Receptors, Virus; D037342:Pertussis Toxin