title: The chemokine receptor CX₃CR1 is directly involved in the arrest of breast cancer cells to the skeleton.
abstract: BACKGROUND
  Skeletal metastases from breast adenocarcinoma are responsible for most of the morbidity and mortality associated with this tumor and represent a significant and unmet need for therapy. The arrival of circulating cancer cells to the skeleton depends first on the adhesive interactions with the endothelial cells lining the bone marrow sinusoids, and then the extravasation toward chemoattractant molecules produced by the surrounding bone stroma.We have previously shown that the membrane-bound and cell-adhesive form of the chemokine fractalkine is exposed on the luminal side of human bone marrow endothelial cells and that bone stromal cells release the soluble and chemoattractant form of this chemokine. The goal of this study was to determine the role of fractalkine and its specific receptor CX₃CR1 in the homing of circulating breast cancer cells to the skeleton.
  
  
  METHODS
  We employed a powerful pre-clinical animal model of hematogenous metastasis, in which fluorescent cancer cells are identified immediately after their arrival to the bone. We engineered cells to over-express either wild-type or functional mutants of CX₃CR1 as well as employed transgenic mice knockout for fractalkine.
  
  
  RESULTS
  CX₃CR1 protein is detected in human tissue microarrays of normal and malignant mammary glands. We also found that breast cancer cells expressing high levels of this receptor have a higher propensity to spread to the skeleton. Furthermore, studies with fractalkine-null transgenic mice indicate that the ablation of the adhesive and chemotactic ligand of CX₃CR1 dramatically impairs the skeletal dissemination of circulating cancer cells. Finally, we conclusively confirmed the crucial role of CX₃CR1 on breast cancer cells for both adhesion to bone marrow endothelium and extravasation into the bone stroma.
  
  
  CONCLUSIONS
  We provide compelling evidence that the functional interactions between fractalkine produced by both the endothelial and stromal cells of bone marrow and the CX₃CR1 receptor on breast cancer cells are determinant in the arrest and initial lodging needed for skeletal dissemination.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102-1101, USA.
authors.forename: Whitney L
authors.initials: WL
authors.lastname: Jamieson-Gladney
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fong
authors.forename: Olimpia
authors.initials: O
authors.lastname: Meucci
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fatatis
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion / Q000235:genetics; D054428:Chemokine CX3CL1 / Q000235:genetics; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009154:Mutation; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; D019707:Receptors, Chemokine