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.
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.
Kitamura
Takanori
T
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Fujishita
Teruaki
T
Loetscher
Pius
P
Revesz
Laszlo
L
Hashida
Hiroki
H
Kizaka-Kondoh
Shinae
S
Aoki
Masahiro
M
Taketo
Makoto M
MM
D000818:Animals; D002454:Cell Differentiation; D019742:Chemokines, CC / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D008024:Ligands; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology / Q000556:secondary*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis
C108814:CCL15 protein, human; C095218:Ccl9 protein, mouse; C515301:Ccr1 protein, mouse; D019742:Chemokines, CC; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9