Hepatobiliary Malignancies

Visualization of stem cell features in human hepatocellular carcinoma enlightened in vivo significance of tumor-host interaction and clinical implication†

  1. Shunsuke Muramatsu1,
  2. Shinji Tanaka1,‡,*,
  3. Kaoru Mogushi2,
  4. Rama Adikrisna1,
  5. Arihiro Aihara1,
  6. Daisuke Ban1,
  7. Takanori Ochiai1,
  8. Takumi Irie1,
  9. Atsushi Kudo1,
  10. Noriaki Nakamura1,
  11. Koh Nakayama3,
  12. Hiroshi Tanaka2,
  13. Shoji Yamaoka4,
  14. Shigeki Arii1

DOI: 10.1002/hep.26345

Additional Information

Author Information

  1. 1

    Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

  2. 2

    Department of Computational Biology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

  3. 3

    Oxygen Biology Unit, Frontier Research Laboratory, Medical Research Institute Tokyo Medical and Dental University, Tokyo, Japan

  4. 4

    Department of Molecular Virology, Tokyo Medical and Dental University, Tokyo, Japan

  1. ‡

    Tel: +81-3-5803-5928; Fax: +81-3-5803-0263

*Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan

  1. †

    This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.26345

  2. ‡

    Tel: +81-3-5803-5928; Fax: +81-3-5803-0263

Publication History

  1. Accepted manuscript online: 27 FEB 2013 03:03PM EST
  2. Manuscript Accepted: 13 FEB 2013
  3. Manuscript Revised: 7 FEB 2013
  4. Manuscript Received: 30 JUN 2012

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Abstract

Background:Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies because of recurrence and/or metastasis even after curative resection. Emerging evidence suggests that tumor metastasis and recurrence might be driven by a small subpopulation of stemness cells, so-called cancer stem cells (CSCs). Previous investigations have revealed that glioma and breast CSCs exhibit intrinsically low proteasome activity and that breast CSCs also reportedly contain a lower reactive oxygen species (ROS) level than corresponding non-tumorigenic cells. Aims: Here, we visualized 2 stem cell features, low proteasome activity and low intracellular ROS, in HCC cells using 2-color fluorescence activated cell sorting to isolate cells with stem cell features. These cells were then analyzed for their division behavior in normoxia and hypoxia, expression of stem cell markers, tumorigenicity, metastatic potential, specific gene expression signatures, and their clinical implications. Results: A visualized small subpopulation of HCC cells demonstrated asymmetric divisions. Their remarkable tumorigenicity in nonobese diabetic/severe combined immunodeficient mice suggested the cancer initiation potential of these HCC CSCs. Comprehensive gene expression analysis revealed that chemokine-related genes were upregulated in the CSCs subpopulation. Our identified HCC CSCs facilitated the migration of macrophages in vitro and demonstrated metastatic potentials via recruitment of macrophages in vivo. In patients who undergo curative operation for HCC, the CSC-specific gene signature in the liver microenvironment significantly correlates with recurrence. Conclusions: Based on these findings, the stem cell feature monitoring system proposed here is a promising tool to analyze the in vivo significance of CSC microenvironments in human HCCs. (HEPATOLOGY 2013.)

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