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

Nat Genet. 2007 Apr;39(4):467-75. doi: 10.1038/ng1997. Epub 2007 Mar 18.


Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using cis-Apc(+/Delta716) Smad4(+/-) mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-beta family signaling is blocked, we show here that a new type of immature myeloid cell (iMC) is recruited from the bone marrow to the tumor invasion front. These CD34(+) iMCs express the matrix metalloproteinases MMP9 and MMP2 and the CC-chemokine receptor 1 (CCR1) and migrate toward the CCR1 ligand CCL9. In adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the cis-Apc/Smad4 mutant, we further show that lack of CCR1 prevents accumulation of CD34(+) iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of transforming growth factor-beta family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Cell Movement / genetics*
  • Chemokines, CC
  • Female
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / pathology
  • Macrophage Inflammatory Proteins / metabolism
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Cells / metabolism*
  • Neoplasm Invasiveness / genetics
  • Receptors, CCR1
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • Smad4 Protein / genetics*
  • Stromal Cells / metabolism
  • Tumor Cells, Cultured


  • Antigens, CD34
  • Ccl9 protein, mouse
  • Ccr1 protein, mouse
  • Chemokines, CC
  • Macrophage Inflammatory Proteins
  • Receptors, CCR1
  • Receptors, Chemokine
  • Smad4 Protein
  • Smad4 protein, mouse
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse

Associated data

  • GEO/GSE6950