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Hepatic Stellate Cells Accelerate the Malignant Behavior of Cholangiocarcinoma Cells

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Although tumor–stromal interaction has been discussed, the role of hepatic stellate (HS) cells against cancer, especially cholangiocarcinoma (CC), has not been clarified. The aim of this study is to investigate the effect of HS cells on CC cell progression in vitro and in vivo.

Methods

The effects of CC conditioned medium (CC-CM) on activation and proliferation of HS cells (LI90 and LX-2), the influences of HS cell CM (HS-CM) on proliferation and invasion of CC cells (HuCCT-1 and RBE), and the effects of their interaction on HUVEC tube formation were assessed using each CM. The effect of HS cells on tumor growth was examined in vivo by subcutaneous co-injection. Cytokine array was performed to assess the secreted proteins induced by their coculture.

Results

CC-CM activated HS cells and increased their proliferation. HS-CM dose-dependently increased CC cell proliferation and invasion. Chemotherapy of CC cells was less effective when treated with HS-CM. HS-CM activated the mitogen-activated protein kinase and Akt pathways in tumor cells. The indirect interaction of CC and HS cells promotes tube formation of human umbilical venous endothelial cells. Subcutaneous co-injection of tumor cells with HS cells in nude mouse resulted in increased tumor size. Several proteins were found in the culture medium induced by their coculture, thought to be key proteins which regulated tumor–stromal interaction.

Conclusions

This study indicates that HS cells play an important role in accelerating cholangiocarcinoma progression and may be a therapeutic target in cholangiocarcinoma.

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Acknowledgment

We thank Mr. Kikuchi K for kind advice regarding statistical analysis.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Hirohisa Okabe MD, Toru Beppu PhD, Hiromitsu Hayashi PhD, Takatoshi Ishiko PhD, Toshiro Masuda PhD, Ryu Otao MD, Hasita Horlad & Hideo Baba PhD

  2. Department of Diagnostic Medicine, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan

    Hirohumi Jono PhD, Mitsuharu Ueda PhD, Satoru Shinriki PhD & Yukio Ando PhD

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  1. Hirohisa Okabe MD
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  2. Toru Beppu PhD
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  12. Hideo Baba PhD
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Corresponding author

Correspondence to Hideo Baba PhD.

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Okabe, H., Beppu, T., Hayashi, H. et al. Hepatic Stellate Cells Accelerate the Malignant Behavior of Cholangiocarcinoma Cells. Ann Surg Oncol 18, 1175–1184 (2011). https://doi.org/10.1245/s10434-010-1391-7

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  • DOI: https://doi.org/10.1245/s10434-010-1391-7

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