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.
Arenberg
D A
DA
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109-0642, USA. darenber@umich.edu
Zlotnick
A
A
Strom
S R
SR
Burdick
M D
MD
Strieter
R M
RM
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