Published online before print June 5, 2008

This Article Full Text (Rapid PDF) All Versions of this Article: ajpath.2008.070732v1 173/1/253    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by van Deventer, H. W. Articles by Serody, J. S. PubMed PubMed Citation Articles by van Deventer, H. W. Articles by Serody, J. S.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070732

Accepted for publication April 14, 2008.

Article

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

^@ To whom correspondence should be addressed. E-mail: hvand{at}med.unc.edu.

	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 -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.