Abstract 2361: Fractalkine and CX3CR1 are involved in the early stages of skeletal metastasis

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Abstract It is estimated that eighty percent of breast cancer (BCa) and ninety percent of prostate cancer (PCa) patients develop late-stage skeletal metastases. Metastatic disease is the major cause of death in these patients and only palliative treatments for clinically established skeletal metastases are available. In order to develop effective preventive and curative therapies, it is essential that mechanisms involved in cancer cell bone colonization are fully understood. Our previous in vitro experiments have shown that the chemokine fractalkine (FKN, CX3CL1) and its receptor, CX3CR1, mediate adhesion of PCa cells to bone marrow endothelial cells as well as their migration toward osteoblasts. We have also shown that CX3CR1 is highly expressed in BCa and PCa cell lines as well as ex vivo prostate and mammary human cancer tissues, whereas FKN is expressed by stromal cells of the bone marrow. Therefore, we hypothesize that FKN and CX3CR1 are involved in the arrival and arrest of cancer cells to the bone during the metastatic process. To test our hypothesis, we employed a mouse model of metastasis in which fluorescent human cancer cells are inoculated in the left cardiac ventricle. Using a histology-stereomicroscopy combination approach, we detect single cancer cells in the bone microenvironment as early as 24 hours after their delivery into the blood stream. Analyses at later time-points also reveal the progression of small cancer foci into macroscopic metastases. Inoculation of PCa or BCa cells in FKN-null mice shows a significant decrease in the number of cancer cells disseminated to the skeleton by hematogenous route. In parallel experiments, exogenous over-expression of CX3CR1 in BCa cells increases their arrival to bone. On the other hand, upon expression of a CX3CR1 functional mutant - unable to mediate adhesion to FKN - the dissemination of BCa cells to the skeleton is significantly impaired. Finally, we used a newly engineered inhibitor of CX3CR1 to counteract skeletal metastases in vivo. In conclusion, our data present strong evidence that the FKN/CX3CR1 pair is involved in the early stages of prostate and breast cancer bone metastasis. Thus, altering the interactions between FKN and its receptor represents an attractive therapeutic approach for the prevention of skeletal metastases from prostate and breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2361.