Article abstract
Nature Genetics 39, 467 - 475 (2007)
Published online: 18 March 2007 | doi:10.1038/ng1997
SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion
Takanori Kitamura1, Kohei Kometani2, Hiroki Hashida3, Akihiro Matsunaga1, Hiroyuki Miyoshi1, Hisahiro Hosogi1, Masahiro Aoki1, Masanobu Oshima1,4, Masakazu Hattori2, Arimichi Takabayashi3, Nagahiro Minato2 & Makoto M Taketo1
Abstract
Inactivation of TGF-
family signaling is implicated in colorectal tumor progression. Using cis-Apc+/
716 Smad4+/- mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF- 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- family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.
- Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
- Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka 530-8480, Japan.
- Present address: Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.
Correspondence to: Makoto M Taketo1 e-mail: taketo@mfour.med.kyoto-u.ac.jp
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