The murine CC chemokine, 6C-kine, inhibits tumor growth and angiogenesis in a human lung cancer SCID mouse model.
The recently described CC chemokine, 6C-kine, is unique in that it contains -six rather than the usual four conserved cysteines typical of this family. Furthermore, murine 6C-kine binds to one of the CXC chemokine receptors CXCR3, in addition to its other known receptor CCR7. We have shown that two other ligands of CXCR3, IP-10 and MIG, are potent inhibitors of tumor growth in severe combined immunodeficiency (SCID) mice. We postulated that murine 6C-kine may also inhibit tumor growth via inhibition of angiogenesis in this model. SCID mice (n = 6 per group) inoculated with A549 human lung cancer cells were treated with either 6C-kine (100 ng intra-tumor injection every other day) or control protein for 8 weeks. Tumors from murine 6C-kine-treated mice (288 +/- 26 mm3) were significantly smaller than tumors from control treated mice (788 +/- 156 mm3, P = 0.005). Additionally, murine 6C-kine reduced metastases compared with controls (0.5 +/- 0.3 vs 3.0 +/- 1.2 metastases per animal, P = 0.05). Tumor vascularity (as assessed by vessel density counting) was reduced in murine 6C-kine-treated mice compared with controls. Murine 6C-kine had no direct effect on proliferation of A549 cells, and there were no differences in the infiltration of leukocyte sub-populations, assessed by flow cytometry, in the treatment groups. Interestingly, human 6C-kine, unlike murine 6C-kine, does not bind CXCR3 and had no anti-tumor effect in the same model. These data suggest that murine 6Ckine has anti-tumor effects independent of its leukocyte-recruiting activity. Furthermore, while not confirmatory, these data lend further support to the fact that CXCR3 may be the receptor for angiostatic CXC chemokines.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109-0642, USA. darenber@umich.edu
D A
DA
Arenberg
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A
Zlotnick
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Strom
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MD
Burdick
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Strieter
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000627:therapeutic use*; D002678:Chimera; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000276:immunology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000502:physiology; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; C515478:CCL21 protein, human; C515187:CXCR3 protein, human; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine