A chemokine receptor antagonist inhibits experimental breast tumor growth.
The leukocyte infiltrate of human and murine epithelial cancers is regulated by chemokine production in the tumor microenvironment. In this article, we tested the hypothesis that chemokine receptor antagonists may have anticancer activity by inhibiting this infiltrate. We first characterized CC chemokines, chemokine receptors, and the leukocyte infiltrate in the 410.4 murine model of breast cancer. We found that CCL5 (RANTES) was produced by the tumor cells, and its receptors, CCR1 and CCR5, were expressed by the leukocyte infiltrate. As Met-CCL5 is an antagonist of CCR1 and CCR5 with activity in models of inflammatory disease, we tested its activity against 410.4 tumors. After 5 weeks of daily treatment with Met-CCL5, the volume and weight of 410.4 tumors was significantly decreased compared with control-treated tumors. Met-CCL5 was also active against established tumors. The total cell number obtained after collagenase digestion was decreased in Met-CCL5-treated tumors as was the proportion of infiltrating macrophages. Furthermore, chemokine antagonist treatment increased stromal development and necrosis. Our results provide direct evidence that macrophages contribute to tumor development and are the first indication that chemokine receptor antagonists may provide novel strategies in cancer prevention and treatment.
Robinson
Stephen C
SC
Cancer Research UK, Translational Oncology Laboratory, Barts and The London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, United Kingdom.
Scott
Kate A
KA
Wilson
Julia L
JL
Thompson
Richard G
RG
Proudfoot
Amanda E I
AE
Balkwill
Frances R
FR
D000818:Animals; D065100:CCR5 Receptor Antagonists; D002455:Cell Division / Q000187:drug effects; D018946:Chemokine CCL5 / Q000096:biosynthesis; D005260:Female; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
C515300:CCR1 protein, human; D065100:CCR5 Receptor Antagonists; C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine