Liver cancer stem cells: Recent progress in basic and clinical research

Abstract

The cancer stem cell (CSC) hypothesis was proposed over 4 decades ago and states that tumor growth is maintained by a small subset of cancer cells analogous to normal tissue stem cells in terms of self-renewal and differentiation capacity. Advances in CSC isolation were initially achieved in hematological malignancies and later in solid tumors, including hepatocellular carcinoma (HCC), the major histological type of liver cancer. Increasing evidence suggests the importance of liver CSCs for tumor growth, metastasis, and chemo/radiation resistance in HCC, but the application of the liver CSC concept for the clinical diagnosis and treatment of HCC has not yet been achieved to the extent initially expected. Furthermore, the heterogeneity and plasticity of liver CSCs has recently been noted and might be related to drug resistance and the rapid growth and/or metastasis of the tumor after treatment. Here, we introduce our recent advancement in liver CSC research and discuss the clinical implications, which may lead to the development of improved diagnostics and treatment in HCC.

Keywords: AFP, alpha-fetoprotein; Alpha-fetoprotein; CD90; CSC, cancer stem cells; Cancer stem cells; EpCAM; HCC, hepatocellular carcinoma; Hepatocellular carcinoma; LG2m, laminin γ2 monomer; Laminin gamma 2 monomer.

Fig. 1

Two distinct liver cancer stem cells. Liver cancer stem cells are a heterogenous population in terms of cellular phenotypes. EpCAM-positive liver cancer stem cells show polygonal epithelial cell shape, express genes associated with epithelial cell function, produce alpha-fetoprotein (AFP), and are highly tumorigenic. In contrast, CD90-positive liver cancer stem cells show mesenchymal cell shape, express genes associated with mesenchymal cell function, produce laminin γ2 monomer (LG2m), and are highly metastatic.

Fig. 2

Plasticity and interaction of hepatocellular carcinoma cells. Heterogenous liver cancer stem cells collaborate to orchestrate the development of hepatocellular carcinoma. EpCAM-positive liver cancer stem cells show activation of Wnt signaling and resistance to sorafenib, especially when tumor suppressor capicua is inactivated. Oncostatin M (OSM) induces hepatocytic differentiation of EpCAM-positive liver cancer stem cells to non-cancer stem cells. EpCAM-positive liver cancer stem cells alone cannot metastasize to distant organs but acquire metastatic ability in the presence of CD90-positive liver cancer stem cells, potentially through paracrine TGF-β signaling. CD90-positive liver cancer stem cells express c-Kit, and sorafenib has no effect on EpCAM-positive HCC cells but suppresses de novo metastasis of hepatocellular carcinoma mediated by CD90-positive liver cancer stem cells, potentially through c-Kit signaling inhibition. Cellular stresses induced by chemotherapeutic reagents such as 5-fluorouracil (5-FU), epirubicin, or transcatheter arterial chemoembolization induce de-differentiation of non-cancer stem cells or transdifferentiation of EpCAM-positive liver cancer stem cells to CD90-positive liver cancer stem cells.

Fig. 3

Molecular hepatocellular carcinoma subclasses and prognosis. Hepatocellular carcinoma (HCC) is molecularly categorized into several subclasses, roughly divided into a poor survival proliferation class or a good survival non-proliferation class. Hoshida's S1 and Boyault's G3 subclass is molecularly associated with the activation of TGF-β/Wnt signaling, presence of CD90-positive liver cancer stem cells, and elevation of serum laminin γ2 monomer (LG2m). Hoshida's S2 and Boyault's G1-2 subclass is molecularly associated with the activation of Myc/Akt signaling, EpCAM-positive liver cancer stem cells, and elevation of serum alpha-fetoprotein (AFP). Some HCCs show high intensity in hepatobiliary phase (HBP) images of Gd-EOB-DTPA-enhanced MRI. Molecularly, these HCCs have CTTNB1 mutations with activation of HNF4A, and patients show good survival outcomes.