Role of the interactions between the chemokine CX3CL1/fractalkine and its receptor CX3CR1 in cell-adhesion and extravasation during the early arrival of circulating cancer cells to the skeleton.

5328 Advanced prostate cancer shows an overwhelming propensity to metastasize to the skeleton, causing patients to experience extreme pain and eventually leading to death in the vast majority of cases. Unfortunately, only palliative treatments for clinically established skeletal metastases are available. It is therefore essential that the mechanisms involved in the initial colonization of the bone marrow by cancer cells are fully understood in order to develop effective preventive treatments.
 We have previously shown that the chemokine fractalkine promotes the adhesion of human prostate cancer (PCa) cells to bone marrow endothelial cells (BMEC) as well as their migration toward human osteoblasts in vitro . We were therefore the first to hypothesize that fractalkine expressed on the surface of BMEC as well as secreted by the cells of the bone microenvironment recruits the CX 3 CR1 receptor expressed by prostate cancer cells to mediate early metastatic events and contributes to their selective colonization of the skeleton.
 To further test this hypothesis, we injected green-fluorescent cancer cells in the left cardiac ventricle of immunocompromised mice that were successively sacrificed between 1 and 72 hours following the injection. A red-fluorescent marker was used to visualize the endothelium in tissue sections of bones that are common sites of secondary tumors in our mouse model of experimental metastases. The correct execution of cell- injection was validated by the inclusion of blue-fluorescent polystyrene beads in the cancer cell suspension. We found that a blocking antibody against CX 3 CR1 significantly reduced the arrival of cells at the bone tissue following their injection in the blood circulation. The blockade of this chemokine receptor was less determinant for counteracting the location of cancer cells to soft tissues. Finally, the role of CX 3 CR1 in skeletal metastasis was confirmed by the alteration of its expression by cancer cells followed by their injection in our animal model.In conclusion, our present data further support the idea that the CX 3 CR1-fractalkine pair is centrally involved in the arrival of prostate cancer cells to the bone and represents an attractive therapeutic target in the prevention of skeletal metastasis from prostate adenocarcinoma.