C-C chemokine receptor 5 on pulmonary fibrocytes facilitates migration and promotes metastasis via matrix metalloproteinase 9.
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 alpha-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.
van Deventer
Hendrik W
HW
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7305, USA. hvand@med.unc.edu
Wu
Qing Ping
QP
Bergstralh
Daniel T
DT
Davis
Beckley K
BK
O'Connor
Brian P
BP
Ting
Jenny P-Y
JP
Serody
Jonathan S
JS
D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology*; D003239:Connective Tissue Cells / Q000378:metabolism*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000556:secondary*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019713:Receptors, CCR5; D020780:Matrix Metalloproteinase 9