Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Recent reports suggest critical roles of bone marrow derived myeloid cells in tumor invasion and metastasis, although these findings have not yet been applied to cancer chemotherapy. Here we present in vivo evidence that supports a novel strategy to target tumor-associated myeloid cells and block liver metastasis of colon cancer. Using mouse models for tumor dissemination to the liver, we show that mouse and human colon cancer cells secrete CC-chemokine ligand (CCL) 9 and CCL15, respectively, and recruit CD34+ Gr-1– immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinase (MMP) 2 and 9. Loss of Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Moreover, a CCR1 antagonist BL5923 significantly prolongs survival of tumor-bearing mice by inhibiting metastatic colonization. These results suggest that CCR1 antagonists can suppress metastatic expansion of human colon cancer cells in the liver by blocking the accumulation of CCR1+ myeloid cells; a novel strategy of “cellular target therapy”