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

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^*

From the Department of Medicine,^* Division of Hematology/Oncology, the Department of Microbiology and Immunology, and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Previously, our group has used a B16-F10 melanoma model to showthat C-C chemokine receptor 5 (CCR5) knockout (CCR5^–/–)mice form fewer pulmonary metastases than wild-type mice. Thisadvantage can be eliminated by injecting CCR5^–/–mice with wild-type pulmonary mesenchymal cells before tumorinjection. In this article, we present the mechanisms underlyingthis finding. First, we demonstrate that wild-type mesenchymalcells 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 migratinginto the lung after intravenous injection (P < 0.01). Theinjection of wild-type but not CCR5^–/– mesenchymalcells led to a 7.0 ± 1.6 (P < 0.05)-fold inductionof matrix metalloproteinase 9 (MMP9) in the host lung. Neitherwild-type nor CCR5^–/– cells caused significant increasesin MMP2, MMP3, or MMP8. Inhibition of the gelatinase activityof MMP9 decreased the number of metastases and restored theadvantage that CCR5^–/– mice have over wild-typemice. Further analysis showed that the CCR5⁺ mesenchymal cellsexpressed CD45⁺ and CD13⁺ but did not express ${alpha}$ -smooth muscleactin. This phenotype is characteristic of a subset of mesenchymalcells called fibrocytes. Together, these data suggest a novelrole for CCR5 in the migration of pulmonary fibrocytes and thepromotion of metastasis.