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

Takanori Kitamura, Teruaki Fujishita, Pius Loetscher, Laszlo Revesz, Hiroki Hashida, Shinae Kizaka-Kondoh, Masahiro Aoki, Makoto M. Taketo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)13063-13068
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume107
Issue number29
DOIs
Publication statusPublished - 20 Jul 2010

Keywords

  • Chemokine
  • Metalloproteinase
  • Stromal cell

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