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Hepatic Stellate Cells Promote Liver Metastasis of Colon Cancer Cells by the Action of SDF-1/CXCR4 Axis

  • Translational Research and Biomarkers
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Abstract

Background

It has been determined that the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1) regulate several key processes in a wide variety of cancers. However, the function and mechanism of the SDF-1/CXCR4 system in the metastasis of colorectal cancer remain controversial.

Methods

Immunohistochemistry was performed to examine quantitatively the expression of CXCR4 in 40 human samples of colorectal cancer and liver metastasis. The functions of SDF-1 on HCT116 colon cancer cells were investigated in vitro. We subcutaneously inoculated HCT116 cells with hepatic stellate cells (HSCs) expressing SDF-1. The CXCR4 inhibitor AMD3100 was tested in vitro and in vivo.

Results

By quantitatively counting the number of cells, it was shown that there are more CXCR4-positive cells at the metastatic site in the liver compared with the primary sites. We demonstrated the effect of SDF-1 on the invasion and antiapoptosis of HCT116 cells in vitro. In mouse experiment of liver metastasis, intraperitoneal administration of AMD3100 blocked the metastatic potential of HCT116 cells. Furthermore, we found that α-smooth muscle actin (α-SMA)-positive myofibroblasts derived from HSCs, surrounding the liver metastasis foci, secreted SDF-1. The subcutaneous inoculation of HCT116 cells with HSCs promoted the tumor initiation in nude mice, indicating the importance of the direct interaction between these cells in vivo.

Conclusion

These results suggest that HSCs play important role in liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis and provide preclinical evidence that blockade of the axis is a target for antimetastasis therapy.

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Authors and Affiliations

  1. Department of Surgery, Graduate School of Medicine, Kyoto University, Shogoin-Kawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Ryo Matsusue MD, Hajime Kubo MD, PhD, Shigeo Hisamori MD, Kae Okoshi MD, PhD, Hidekazu Takagi MD, Koya Hida MD, Keiko Nakano MSci, Atsushi Itami MD, PhD, Kenji Kawada MD, PhD, Satoshi Nagayama MD, PhD & Yoshiharu Sakai MD, PhD

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  1. Ryo Matsusue MD
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  2. Hajime Kubo MD, PhD
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  3. Shigeo Hisamori MD
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  4. Kae Okoshi MD, PhD
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  5. Hidekazu Takagi MD
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  6. Koya Hida MD
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  7. Keiko Nakano MSci
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  8. Atsushi Itami MD, PhD
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  9. Kenji Kawada MD, PhD
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  10. Satoshi Nagayama MD, PhD
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  11. Yoshiharu Sakai MD, PhD
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Correspondence to Hajime Kubo MD, PhD.

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Matsusue, R., Kubo, H., Hisamori, S. et al. Hepatic Stellate Cells Promote Liver Metastasis of Colon Cancer Cells by the Action of SDF-1/CXCR4 Axis. Ann Surg Oncol 16, 2645–2653 (2009). https://doi.org/10.1245/s10434-009-0599-x

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  • DOI: https://doi.org/10.1245/s10434-009-0599-x

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