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Role of Bone Marrow-Derived CCR1+ Cells in Colon Cancer Invasion and Metastasis

  • Makoto Mark Taketo

Abstract

Loss of transforming growth factor (TGF)-β family signaling is implicated in colorectal cancer (CRC) progression. Using cis-Apc +/Δ716 Smad4 +/− mutant (cis-Apc/Smad4) mice, a model of invasive CRC whose TGF-β family signaling is blocked, we have found that immature myeloid cells (iMCs) are recruited from the bone marrow to the tumor invasion front. These iMCs express the matrix metalloproteinases MMP9 and MMP2 and the CC-chemokine receptor 1 (CCR1), and migrate towards the CCR1 ligand CCL9. By deleting Ccr1 in the background of the cis-Apc/Smad4 mutant, we have shown an accumulation of iMCs at the invasion front and suppression of tumor invasion. Furthermore, mouse and human CRC cells secrete CCR1 ligands CCL9 and CCL15, respectively, and recruit the CCR1-expressing iMCs. Loss of the Ccr1, Mmp2, or Mmp9 gene in the host mice dramatically suppresses outgrowths of disseminated tumors in the liver. Consistently, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization, and significantly prolongs the survival of tumor-bearing mice. These results indicate that loss of TGF-β family signaling in CRC epithelium causes accumulation of iMCs that promote tumor invasion, and that CCR1 antagonists can provide anti-metastatic therapies for patients with disseminated CRC cells in the liver.

Keywords

TGF-β Immature myeloid cells Matrix metalloproteinase Chemokine receptor CCR1 

Notes

Acknowledgment

The author would like to thank the collaborators of this project, which has been published in (Kitamura et al. 2010), and the publisher, The National Academy of Sciences of the United States of America, for allowing partial re-publication of the contents here.

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Copyright information

© Springer Japan 2015

Authors and Affiliations

  1. 1.Department of Pharmacology, Graduate School of MedicineKyoto UniversitySakyo, KyotoJapan

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