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, 6 (1), 29-40

The Biology of Cancer Stem Cells and Its Clinical Implication in Hepatocellular Carcinoma

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The Biology of Cancer Stem Cells and Its Clinical Implication in Hepatocellular Carcinoma

Seung Kew Yoon. Gut Liver.

Abstract

Hepatocellular carcinoma (HCC) is a highly malignant tumor with limited treatment options in its advanced state. The molecular mechanisms underlying HCC remain unclear because of the complexity of its multi-step development process. Cancer stem cells (CSCs) are defined as a small population of cells within a tumor that possess the capability for self-renewal and the generation of heterogeneous lineages of cancer cells. To date, there have been two theories concerning the mechanism of carcinogenesis, i.e., the stochastic (clonal evolution) model and the hierarchical (cancer stem cell-driven) model. The concept of the CSC has been established over the past decade, and the roles of CSCs in the carcinogenic processes of various cancers, including HCC, have been emphasized. Previous experimental and clinical evidence indicated the existence of liver CSCs; however, the potential mechanistic links between liver CSCs and the development of HCC in humans are not fully understood. Although definitive cell surface markers for liver CSCs have not yet been found, several putative markers have been identified, which allow the prospective isolation of CSCs from HCC. The identification and characterization of CSCs in HCC is essential for a better understanding of tumor initiation or progression in relation to signaling pathways. These markers could be used along with clinical parameters for the prediction of chemoresistance, radioresistance, metastasis and survival and may represent potential targets for the development of new molecular therapies against HCC. This review describes the current evidence for the existence and function of liver CSCs and discuss the clinical implications of CSCs in patients demonstrating resistance to conventional anti-cancer therapies, as well as clinical outcomes. Such data may provide a future perspective for targeted therapy in HCC.

Keywords: Cancer stem cell; Hepatocellular carcinoma; Stem cell.

Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Fig. 1
Fig. 1
Two general models for tumorigenesis. The stochastic model claims that every cancer cell in a tumor can ultimately acquire a capacity for self-renewal and multilineage potency, thereby forming new tumors (A), whereas the hierarchy model claims that cancer cells in a tumor are heterogeneous and that only a minority of these cells serves as cancer stem cells (CSCs), thus giving rise to tumors (B).
Fig. 2
Fig. 2
The signaling pathways linked to hepatic cancer stem cells (CSCs) in hepatocarcinogenesis. Key signaling pathways that regulate the function of hepatic CSCs include Wnt/β-catenin, transforming growth factor (TGF-β), Hedgehog, Notch, and MYC. Epithelial cell adhesion molecule (EpCAM) is a Wnt/β-catenin signaling target gene, and activation of Wnt/β-catenin signaling regulates EpCAM expression in hepatocellular carcinoma (HCC) cell lines. In CD133+ HCC cells, Wnt/β-catenin, Notch1, and smoothened (SMO)/Hedgehog signaling pathways are linked with self-renewal, differentiation, and proliferation of hepatic CSCs. Targeting of these critical pathways in the regulation of hepatic CSCs may be a promising tool for the development of new therapies to eradicate tumor cells completely in HCC. Gli3, glioma-associated oncogene family zinc finger 3; TACE, TNF-alpha converting enzyme; PTC, patched.
Fig. 3
Fig. 3
The roles of hepatic cancer stem cells (CSCs) in tumorigenesis and treatment resistance in hepatocellular carcinoma. Normal stem cells self-renew and can differentiate into progenitor cells, which eventually differentiate into fully differentiated hepatocytes. CSCs can arise from normal stem cells, progenitor cells and even differentiated hepatocytes when oncogenic events occur during cellular processes. The expansion of hepatic CSCs results in the formation of the primary tumor, which is composed of a heterogeneous mass of cancer cells. The unlimited proliferation of hepatic CSCs promotes tumor growth and can give rise to distant metastases that occur in conjunction with the angiogenic process. When chemotherapy or radiotherapy is used, hepatic CSCs play an essential role in treatment resistance and can produce tumor recurrence.

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