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C-C Chemokine Receptor 5 on Pulmonary Fibrocytes Facilitates Migration and Promotes Metastasis via Matrix Metalloproteinase 9

By Hendrik W. van Deventer, Qing Ping Wu, Daniel T. Bergstralh, Beckley K. Davis, Brian P. O'Connor, Jenny P.-Y. Ting and Jonathan S. Serody


Previously, our group has used a B16-F10 melanoma model to show that C-C chemokine receptor 5 (CCR5) knockout (CCR5−/−) mice form fewer pulmonary metastases than wild-type mice. This advantage can be eliminated by injecting CCR5−/− mice with wild-type pulmonary mesenchymal cells before tumor injection. In this article, we present the mechanisms underlying this finding. First, we demonstrate that wild-type mesenchymal cells migrate to CCL4 more efficiently in vitro than CCR5−/− cells. Wild-type mesenchymal cells were also 3.6 (1.85 to 5.85) times more efficient than CCR5−/− cells at migrating into the lung after intravenous injection (P < 0.01). The injection of wild-type but not CCR5−/− mesenchymal cells led to a 7.0 ± 1.6 (P < 0.05)-fold induction of matrix metalloproteinase 9 (MMP9) in the host lung. Neither wild-type nor CCR5−/− cells caused significant increases in MMP2, MMP3, or MMP8. Inhibition of the gelatinase activity of MMP9 decreased the number of metastases and restored the advantage that CCR5−/− mice have over wild-type mice. Further analysis showed that the CCR5+ mesenchymal cells expressed CD45+ and CD13+ but did not express α-smooth muscle actin. This phenotype is characteristic of a subset of mesenchymal cells called fibrocytes. Together, these data suggest a novel role for CCR5 in the migration of pulmonary fibrocytes and the promotion of metastasis

Topics: Regular Articles
Publisher: American Society for Investigative Pathology
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Provided by: PubMed Central
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