SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion |
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Authors: | Kitamura Takanori Kometani Kohei Hashida Hiroki Matsunaga Akihiro Miyoshi Hiroyuki Hosogi Hisahiro Aoki Masahiro Oshima Masanobu Hattori Masakazu Takabayashi Arimichi Minato Nagahiro Taketo Makoto M |
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Institution: | Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. |
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Abstract: | 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. |
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