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SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion

Takanori Kitamura1, Kohei Kometani, Hiroki Hashida

  • 1Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.

Nature Genetics
|March 21, 2007
PubMed

Insights

Loss of TGF-beta signaling in colorectal cancer recruits immature myeloid cells (iMCs) that promote invasion. Blocking CCR1 signaling prevents iMC accumulation and suppresses tumor spread.

Area of Science:

  • Oncology
  • Cell Biology
  • Immunology

Background:

  • Transforming growth factor-beta (TGF-beta) signaling is crucial in tumor suppression.
  • Inactivation of TGF-beta signaling is linked to colorectal cancer progression.

Purpose of the Study:

  • To investigate the role of immature myeloid cells (iMCs) in colorectal tumor invasion.
  • To elucidate the mechanism by which TGF-beta pathway inactivation promotes tumor spread.

Main Methods:

  • Utilized cis-Apc(+/Delta716) Smad4(+/-) mutant mice, a model for invasive colorectal cancer with blocked TGF-beta signaling.
  • Analyzed the recruitment and characteristics of iMCs at the tumor invasion front.
  • Investigated the role of CC-chemokine receptor 1 (CCR1) and its ligand CCL9 in iMC migration and tumor invasion using gene deletion models.

Main Results:

  • Identified a novel population of CD34(+) iMCs recruited from bone marrow to the tumor invasion front.
  • These iMCs express matrix metalloproteinases (MMP9, MMP2) and CCR1, migrating towards CCL9.
  • CCL9 expression was elevated in tumor epithelium of adenocarcinomas.
  • Deleting Ccr1 abolished iMC accumulation and significantly suppressed tumor invasion.

Conclusions:

  • Loss of TGF-beta signaling in colorectal tumors drives the recruitment of iMCs.
  • The CCR1-CCL9 axis mediates iMC accumulation and promotes tumor invasion.
  • Targeting iMC recruitment via CCR1 inhibition represents a potential therapeutic strategy for colorectal cancer.

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