Clinical implications of cancer stem cell biology in hepatocellular carcinoma

Abstract

Solid tumors are thought to contain cancer stem cells (CSCs) as a distinct population responsible for tumor relapse and metastasis due to their abilities to self-renew, differentiate, and give rise to a new tumor in local or distant organs. CSCs have been identified in many tumor types, including hepatocellular carcinoma (HCC), the fifth most common and third most deadly malignancy with observable heterogeneity. Numerous studies have shown that hepatic CSCs could be enriched via different cell surface markers, eg, CD13, CD24, CD44, CD90, CD133, EpCAM (CD326), and OV6. They also could be identified through functional assays such as isolating the side population cells by Hoechst dye staining or screening cells with a high activity of aldehyde dehydrogenase. Functional characterization of hepatic CSCs has revealed several deregulated signaling pathways, such as Wnt/β-catenin, AKT, transforming growth factor-beta (TGF-β), interleukin (IL)-6/STAT3 pathways to be critical in inducing "stemness" of HCC and in promoting self-renewal, tumorigenicity, and chemoresistance. An increased understanding of hepatic CSC biology facilitated the development of new diagnostic, prognostic, and therapeutic strategies for improving HCC clinical management. In this review, we summarize recent evidence including the identification of the hepatic CSC and its underlying biological mechanisms, and discuss the potential clinical implications in HCC.

Figure 1. Tumor initiation and metastasis in HCC based on cancer stem cell model

Hepatic CSCs could be derived from hematopoietic stem cells, hepatic stem cells upon somatic mutations of oncogenes and tumor suppressor genes to acquire a tumorigenic potential, or reprogrammed from differentiated hepatic cells to be de-differentiated tumor cells by mutations to acquire the stem cell-like capacity to self-renew and differentiate. These hepatic CSCs eventually expand to a HCC bulk with heterogeneity through self-renewal and differentiation. Moreover, the existence of hepatic CSCs is considered to be responsible to metastasis and recurrence after resection due to its resistance to conventional therapies and its ability of giving rise to a new tumor in local or distant organs.

Figure 2. Signaling Pathways Altered in Hepatic Cancer Stem Cells

Wnt/β-catenin, AKT, TGF-β and IL-6/STAT3 signaling pathways are deregulated in hepatic CSCs. Activation of the Wnt pathway results in β-catenin accumulation in the cytosol and translocation into the nucleus, where β-catenin transcriptional activates the expression of its targets, such as cyclinD1, EpCAM, and miR-181. AKT is activated by two phosphorylation sites Thr308 and Ser473. Phosphorylation of Thr308 is promoted by PI3K and suppressed by PTEN. Activated AKT protect hepatic CSCs from apoptosis through the induction of BCL-2 and ABCG2 under the pressure of chemotherapy. Activated AKT could also interact with HIF-1α to induce VEGF and PDGF-BB expression for regulating the homeostasis and drug resistance of hepatic CSCs. Impaired TGF TGF-β signaling together with activation of IL-6/STAT3 pathway is important to regulate the differentiation and chemoresistance of EpCAM⁺ hepatic CSCs. Studies have shown that these pathways are interconnected, which may further promote stemness and carcinogenesis in HCC.

Figure 3. CSC features, deregulated molecular signaling pathways in hepatic CSCs, and corresponding therapeutic strategies targeting CSCs in HCC

Similar to other tumors, HCC CSCs also possess three CSC features which include the abilities to self-renew and differentiate, tumorigenicity, and chemo/radio-therapeutic resistance. Functional characterization of hepatic CSCs have identified several signaling pathways including Wnt/β-catenin, AKT, TGF-β and IL6 pathways to be important in regulating hepatic CSCs. Further studies based on these identified molecular mechanisms have revealed potential therapeutic strategies by targeting the abilities of CSCs to self-renew, to be tumorigenic and to develop chemoresistance.