Article first published online: 27 MAY 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 58, Issue 1, pages 218–228, July 2013
How to Cite
Muramatsu, S., Tanaka, S., Mogushi, K., Adikrisna, R., Aihara, A., Ban, D., Ochiai, T., Irie, T., Kudo, A., Nakamura, N., Nakayama, K., Tanaka, H., Yamaoka, S. and Arii, S. (2013), Visualization of stem cell features in human hepatocellular carcinoma reveals in vivo significance of tumor-host interaction and clinical course. Hepatology, 58: 218–228. doi: 10.1002/hep.26345
Potential conflict of interest: Nothing to report.
Supported by Grant-in-Aid for Scientific Research on Innovative Areas, Scientific Research (A), Project of Development of Innovative Research on Cancer Therapeutics from Ministry of Education, Culture, Sports, Science & Technology of Japan, and Health & Labour Sciences Research Grant from Ministry of Health Labour & Welfare of Japan.
- Issue published online: 24 JUN 2013
- Article first published online: 27 MAY 2013
- Accepted manuscript online: 27 FEB 2013 03:03PM EST
- Manuscript Accepted: 13 FEB 2013
- Manuscript Received: 30 JUN 2012
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 nontumorigenic cells. Here we visualized two stem cell features, low proteasome activity and low intracellular ROS, in HCC cells using two-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. 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 up-regulated in the CSCs subpopulation. Our identified HCC CSCs facilitated the migration of macrophages in vitro and demonstrated metastatic potential by way of 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. Conclusion: 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;)