[Frontiers in Bioscience E4, 1157-1169, January 1, 2012]

Hepatocellular carcinoma stem cells: origins and roles in hepatocarcinogenesis and disease progression

Yi Shen1, Deliang Cao1

1Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine. 913 N. Rutledge Street, Springfield, IL 62794, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Stem cells and liver development and regeneration
3.1. Liver development
3.2. Liver regeneration
3.3. Effects of liver regenerating process on tumor growth
4. Liver stem cells and hepatocellular carcinoma
4.1. Cellular origins of hepatocellular carcinoma
4.2. Malignant transformation of liver stem/progenitor cells
4.2.1. Hepatocytes
4.2.2. Hepatic progenitor cells (oval cells)
4.2.3. Bone marrow stem cells
4.3. Precursor lesions in the evolution of hepatocellular carcinoma
5. Hepatocellular carcinoma stem cells
5.1. Cancer stem cells
5.2. Deregulation of cell cycle during hepatocarcinogenesis
5.3. Cell surface marker and tumorigenicity of hepatocellular carcinoma stem cells
5.4. Cancer stem cell signaling in hepatocellular carcinoma
5.4.1. Angiogenic signaling
5.4.2. Wnt/β-catenin pathway
5.4.3. Hedgehog signaling
6. Therapeutic implications
7. Acknowledgement
8. References

1. ABSTRACT

Hepatocellular carcinoma (HCC) is a treatment-resistant malignancy with an increasing incidence worldwide. More than 500,000 individuals suffer from this disease annually. Risk factors for human HCC include hepatitis B and C infections, dietary aflatoxin, alcohol abuse, smoking, and oral contraceptive use. Accumulating evidence suggests that liver stem cells play a critical role in HCC development and progression. Dedifferentiated hepatocytes, hepatic oval cells and bone marrow cells are the three major types of liver stem cells, and CD133, CD90, and EpCAM are identified as specific antigenic markers for HCC stem cells. Wnt, Hedgehog, and the angiogenic signalings are main pathways that regulate the HCC stem cell self-renewal and pluripotential, and may be potential targets for novel therapeutic strategies of this malignancy. This review article provides an update in the studies of live and HCC stem cells.