The murine CC chemokine, 6C-kine, inhibits tumor growth and angiogenesis in a human lung cancer SCID mouse model |
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| Authors: | Douglas A Arenberg Albert Zlotnick Scott R B Strom Marie D Burdick Robert M Strieter |
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| Institution: | (1) Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0642, USA, US;(2) DNAX Research Institute, Palo Alto, CA 94394-1104, USA, US;(3) Department of Medicine, Division of Pulmonary & Critical Care Medicine, University of California Los Angeles (UCLA), Los Angeles, CA 90095-1690, USA, US;(4) University of Michigan Medical Center, Division of Pulmonary and Critical Care, 6301 MSRB III, Box 0642, 1150W. Medical Center Drive, Ann Arbor, MI 48109, USA e-mail: darenber@umich.edu Tel.: +1-734-9362612; Fax: +1-734-7644556, US |
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| Abstract: | 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 6C-kine 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.
Received: 15 June 2000 / Accepted: 18 August 2000 |
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| Keywords: | Cytokine Angiogenesis Animal models Tumor |
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