SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion.
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.
Kitamura
Takanori
T
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Kometani
Kohei
K
Hashida
Hiroki
H
Matsunaga
Akihiro
A
Miyoshi
Hiroyuki
H
Hosogi
Hisahiro
H
Aoki
Masahiro
M
Oshima
Masanobu
M
Hattori
Masakazu
M
Takabayashi
Arimichi
A
Minato
Nagahiro
N
Taketo
Makoto M
MM
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics*; D019742:Chemokines, CC; D005260:Female; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; C095218:Ccl9 protein, mouse; C515301:Ccr1 protein, mouse; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse