Da. Arenberg et al., The murine CC chemokine, 6C-kine, inhibits tumor growth and angiogenesis in a human lung cancer SCID mouse model, CANCER IMMU, 49(11), 2001, pp. 587-592
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 C
XCR3, 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 growt
h in severe combined immunodeficiency (SCID) mice. We postulated that murin
e 6C-kine may also inhibit tumor growth via inhibition of angiogenesis in t
his model. SCID mice (n = 6 per group) inoculated with A549 human lung canc
er cells were treated with either 6C-kine (100 ng intra-tumor injection eve
ry other day) or control protein for 8 weeks. Tumors from murine 6C-kine-tr
eated mice (288 +/- 26 mm(3)) were significantly smaller than tumors from c
ontrol treated mice (788 +/- 156 mm(3), 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 cel
ls, and there were no differences in the infiltration of leukocyte sub-popu
lations, 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. Furth
ermore, while not confirmatory, these data lend further support to the fact
that CXCR3 may be the receptor for angiostatic CXC chemokines.