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

Nature Genetics volume 39, pages 467475 (2007) | Download Citation

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Abstract

Inactivation of TGF-β family signaling is implicated in colorectal tumor progression. Using cis-Apc+/Δ716 Smad4+/− mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-β 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-β family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.

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Acknowledgements

We thank T. Hirai for sectioning the clinical samples. We also thank M. Okabe (Osaka University) for EGFP transgenic mice and P.M. Murphy (National Institute of Allergy and Infectious Diseases, US National Institutes of Health) for CCR1 knockout mice. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports and Technology of Japan (to M.M.T.).

Author information

Author notes

    • Masanobu Oshima

    Present address: Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.

Affiliations

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

    • Takanori Kitamura
    • , Akihiro Matsunaga
    • , Hiroyuki Miyoshi
    • , Hisahiro Hosogi
    • , Masahiro Aoki
    • , Masanobu Oshima
    •  & Makoto M Taketo
  2. Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.

    • Kohei Kometani
    • , Masakazu Hattori
    •  & Nagahiro Minato
  3. Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka 530-8480, Japan.

    • Hiroki Hashida
    •  & Arimichi Takabayashi

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Makoto M Taketo.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Construction of cis-Apc/Smad4.

  2. 2.

    Supplementary Fig. 2

    CD34+ CD31 cells.

  3. 3.

    Supplementary Fig. 3

    Expression of CCL9.

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    Supplementary Fig. 4

    Extent of immune cell infiltration.

  5. 5.

    Supplementary Fig. 5

    Extent of CD34+ cell accumulation.

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    Supplementary Fig. 6

    CD34+ cells also express MMP2.

  7. 7.

    Supplementary Table 1

    Array data for chemokine mRNAs.

  8. 8.

    Supplementary Table 2

    List of primer sequences.

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DOI

https://doi.org/10.1038/ng1997

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