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
- 29 June 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 107 (29), 13063-13068
- https://doi.org/10.1073/pnas.1002372107
Abstract
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.Keywords
This publication has 39 references indexed in Scilit:
- Learning therapeutic lessons from metastasis suppressor proteinsNature Reviews Cancer, 2009
- Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc Δ716 miceProceedings of the National Academy of Sciences, 2008
- MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is notBritish Journal of Cancer, 2008
- Microenvironmental regulation of metastasisNature Reviews Cancer, 2008
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Abrogation of TGFβ Signaling in Mammary Carcinomas Recruits Gr-1+CD11b+ Myeloid Cells that Promote MetastasisCancer Cell, 2008
- Clinical Relevance of the Expression of mRNA of MMP-7, MMP-9, TIMP-1, TIMP-2 and CEA Tissue Samples from Colorectal Liver MetastasesTumor Biology, 2007
- Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapyNature Reviews Cancer, 2006
- Dissemination and growth of cancer cells in metastatic sitesNature Reviews Cancer, 2002
- New functions for the matrix metalloproteinases in cancer progressionNature Reviews Cancer, 2002