Novel therapeutic strategies for targeting liver cancer stem cells

Abstract

The cancer stem cell (CSC) hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment.Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It is believed that hepatic progenitor cells (HPCs) could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC. Here we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for targeting liver CSCs.

Keywords: BMI-1 signaling; Cholangiocellular carcinoma; EpCAM; Hedgehog signaling; Hepatocellular carcinoma; Lin-28; Liver cancer stem cell; Notch signaling; Self-protection; Self-renewal; TGF-β signaling; Wnt/β-catenin signaling; miR-181.

Figure 1

Implication of Stem Cells in Liver Development and Hepatic Tumorigenesis. Normal hepatic stem cells are characterized by their ability to self-renew and differentiate, which leads to formation of a normal liver tissues. Oncogenic mutations in normal stem/progenitor cells or even in differentiated cells enhance or endow the cells with self-renewal capability. Consequently, these cells function as cancer stem cells and contribute to the formation of bulk tumors.

Figure 2

Let-7 and Lin28 in Development and Tumorigenesis. (Top) During normal development, the RNA-binding protein Lin28 is highly expressed in stem and progenitor cells. Lin28 blocks processing of let-7 miRNA precursor molecules into mature miRNAs, thereby maintains expression of genes that drive self-renewal and proliferation. As progenitor cells differentiate, Lin28 expression decreases, which allows let-7 processing and increased production of mature let-7 miRNAs. Let-7 miRNAs repress the expression of genes involved in self-renewal resulting in lineage commitment and terminal differentiation. (Bottom) Many molecules contribute to the balancing act of the Lin28/let-7 link in cellular differentiation and tumor progression. An imbalance between Lin28 and let-7 induced by these molecules can result in cellular transformation.

Figure 3

Potential Signalling Pathways of Wnt/β-Catenin, EpCAM and miR-181 Activated in Hepatic Cancer Stem Cells. Upon cleavage by TACE/PS-2, EpICD translocates into the nucleus in a multiprotein complex. Together with FHL2, β-catenin and Lef-1, EpICD contacts DNA at Lef-1 consensus sites. Owing to its ability to inhibit E-cadherin-mediated adhesion, EpCAM provides itself with β-catenin as a central interacting protein.

Figure 4

Strategies in Eradicate Liver Cancer Stem Cells. CSCs are protected from conventional therapies by changing their microenvironment and self-protection. Specifically targeting any of these areas may lead to the eradication of the CSCs.