%0 Journal Article
%T The chemokine receptor CX3CR1 is directly involved in the arrest of breast cancer cells to the skeleton
%A Whitney L Jamieson-Gladney
%A Yun Zhang
%A Alan M Fong
%A Olimpia Meucci
%A Alessandro Fatatis
%J Breast Cancer Research
%D 2011
%I BioMed Central
%R 10.1186/bcr3016
%X 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.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.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.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.Currently, only six percent of women that are first diagnosed with breast adenocarcinoma present with metastases [1]. Unfortunately, between 20 and 50% of them will eventually develop a metastatic disease [1]. Metastases are responsible for an intolerably high number of deaths among patients that would otherwise be almost invariably cured by surgical resection and adj
%U http://breast-cancer-research.com/content/13/5/R91