Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model
Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model
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DOI：
10.1073/pnas.1002372107
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发表时间：
2010-07-20
影响因子：
11.1
通讯作者：
Taketo, Makoto M.
中科院分区：
文献类型：
--
作者：
Kitamura, Takanori;Fujishita, Teruaki;Taketo, Makoto M.
最近的报道表明髓样细胞在肿瘤侵袭和转移中的关键作用，尽管这些发现还没有导致治疗。使用小鼠肝脏播散模型，我们发现小鼠和人结肠癌细胞分别分泌CC-趋化因子配体CCL 9和CCL 15，并招募CD 34（+）Gr-1（-）未成熟髓样细胞（iMC）。它们表达CCL 9/15受体CCR 1并产生基质金属蛋白酶MMP 2和MMP 9。宿主中Ccr 1、Mmp 2或Mmp 9基因的缺乏显著抑制了肝脏中播散性肿瘤的生长。重要的是，CCR 1拮抗剂BL 5923阻断iMC积累和转移定植，并显著延长荷瘤小鼠的生存期。这些结果表明，CCR 1拮抗剂可以为肝脏播散性结肠癌患者提供抗转移治疗。
Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CC-chemokine ligands CCL9 and CCL15, respectively, and recruit CD34(+) Gr-1(-) immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.