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

Nature Genetics volume 39, pages 467–475 (2007)Cite this article

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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Figure 1: CD34+ cells are clustered at the tumor invasion front in cis-Apc/Smad4 mice.
Figure 2: CD34+ cap cells are bone marrow–derived immature myeloid cells.
Figure 3: Expression of CCL9 is increased in the tumor epithelium in cis-Apc/Smad4 mice.
Figure 4: CD34+ iMCs express the cognate CCL9 receptor CCR1 and migrate toward the ligand.
Figure 5: Lack of CCR1 inhibits accumulation of CD34+ iMCs and suppresses tumor invasion.
Figure 6: CD34+ iMCs show gelatinolytic activities by secretion of MMP9 and MMP2.
Figure 7: Infiltrating leukocytes express MMP9 and CCR1 in human colon cancer.

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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.).

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Author notes

  1. Masanobu Oshima

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

Authors and 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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Supplementary information

Supplementary Fig. 1

Construction of cis-Apc/Smad4. (PDF 120 kb)

Supplementary Fig. 2

CD34+ CD31− cells. (PDF 273 kb)

Supplementary Fig. 3

Expression of CCL9. (PDF 46 kb)

Supplementary Fig. 4

Extent of immune cell infiltration. (PDF 483 kb)

Supplementary Fig. 5

Extent of CD34+ cell accumulation. (PDF 461 kb)

Supplementary Fig. 6

CD34+ cells also express MMP2. (PDF 221 kb)

Supplementary Table 1

Array data for chemokine mRNAs. (PDF 42 kb)

Supplementary Table 2

List of primer sequences. (PDF 29 kb)

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Kitamura, T., Kometani, K., Hashida, H. et al. SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat Genet 39, 467–475 (2007). https://doi.org/10.1038/ng1997

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