C-C chemokine receptor 5 on pulmonary fibrocytes facilitates migration and promotes metastasis via matrix metalloproteinase 9.

Abstract

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.

• Authors: Hendrik W van Deventer, Qing Ping Wu, Daniel T Bergstralh, Beckley K Davis, Brian P O'Connor, Jenny P-Y Ting, Jonathan S Serody
• Journal: The American journal of pathology (Am J Pathol) Vol. 173 Issue 1 Pg. 253-64 (Jul 2008) ISSN: 1525-2191 [Electronic] United States
• PMID: 18535183 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Receptors, CCR5
• Matrix Metalloproteinase 9

Topics

• Animals
• Blotting, Western
• Cell Movement (physiology)
• Connective Tissue Cells (metabolism)
• Flow Cytometry
• Immunohistochemistry
• Lung Neoplasms (secondary)
• Matrix Metalloproteinase 9 (metabolism)
• Melanoma, Experimental (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Neoplasm Invasiveness (pathology)
• Neoplasm Metastasis (pathology)
• Oligonucleotide Array Sequence Analysis
• Receptors, CCR5 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction