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C-C Chemokine Receptor 5 on Stromal Cells Promotes Pulmonary Metastasis

Divisions of ¹ Hematology/Oncology and ² Pulmonary and Critical Care Medicine, Department of Medicine; ³ Department of Microbiology and Immunology; and ⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Requests for reprints: Hendrik W. van Deventer, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Room 3009, Old Clinic Building, Chapel Hill, NC 27599-7305. Phone: 919-966-3835; Fax: 919-966-6735; E-mail: hvand{at}med.unc.edu.

We have shown that mice that express the C-C chemokine receptor 5 (CCR5) have enhanced local tumor growth and an impaired response to vaccine therapy compared with CCR5 knockout (CCR5^–/–) mice. Here, we extend these observations to evaluate the function of CCR5 in pulmonary metastasis and the mechanism underlying the diminished tumor growth in CCR5^–/– mice. Lung metastases were counted in wild-type (WT) and CCR5^–/– mice following the injection of 1 x 10⁶ B16-F10 melanoma cells. These results were compared with those from syngeneic bone marrow chimeric mice formed by the transfer of WT bone marrow into irradiated CCR5^–/– and CCR5^–/– marrow into irradiated WT mice. Intact CCR5^–/– mice developed fewer metastases than WT mice (40.2 versus 70.6; P < 0.05). Bone marrow chimeras formed by the transfer of WT bone marrow into CCR5^–/– hosts had fewer metastases than WT hosts injected with knockout marrow (46.6 versus 98.6; P < 0.01). Adoptive transfer of CCR5-expressing leukocytes also failed to promote metastasis in CCR5^–/– mice. However, the i.v. transfer of WT pulmonary stromal cells into CCR5^–/– mice increased the number of metastases compared with transfer of CCR5^–/– stromal cells (102.8 versus 26.0; P < 0.05). These results show for the first time that CCR5 expression on stromal and not hematopoietic cells contributes to tumor metastasis. Therefore, recently developed CCR5 inhibitors may have a novel benefit in cancer therapy.

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