Cancer stemness in hepatocellular carcinoma: mechanisms and translational potential

Abstract

Cancer stemness, referring to the stem-cell-like phenotype of cancer cells, has been recognised to play important roles in different aspects of hepatocarcinogenesis. A number of well-established cell-surface markers already exist for liver cancer stem cells, with potential new markers of liver cancer stem cells being identified. Both genetic and epigenetic factors that affect various signalling pathways are known to contribute to cancer stemness. In addition, the tumour microenvironment—both physical and cellular—is known to play an important role in regulating cancer stemness, and the potential interaction between cancer stem cells and their microenvironment has provided insight into the regulation of the tumour-initiating ability as well as the cellular plasticity of liver CSCs. Potential specific therapeutic targeting of liver cancer stemness is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcome by reducing chemoresistance.

Emerging Role of E2F Family in Cancer Stem Cells

“…In summary, CSC populations are dynamic populations with high cellular plasticity. In heterogeneous tumor cell populations, cells can undergo phenotypic switching between CSCs and tumor cells phenotype, a phenomenon that is essential for tumor progression and recurrence ( 61 , 62 ).…”

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

“…The first FDA-approved epidrugs were DNMT and HDAC inhibitors for the treatment of haematological malignancies. 31 , 129 , 130 The experimental and clinical experience gathered over the past years has shown us that: i) these specific but at the same time “globally acting” agents can reprogramme cancer stemness through their interaction with multiple genes and pathways, inhibiting cancer initiation and progression; 129 , 131 ii) long-lasting cancer cell reprogramming, and therefore improved activity, can be achieved at low and less toxic doses of epidrugs; 129 , 132 iii) epidrugs can overcome primary resistance and restore sensitivity of cancer cells to targeted agents and conventional chemotherapeutics; 129 , 133 , 134 iv) epigenetic alterations in cells of the tumour microenvironment (TME), both stromal and immune cells, contribute to carcinogenesis and can be targeted to enhance therapeutic efficacy. Indeed, recent evidence indicates that targeting different epigenetic regulators, including writers (DNMTs and HMTs), readers (BRDs) and erasers (HDACs, KDMs) can increase immune recognition of tumour cells and synergise with immunotherapy.…”

Development of a Predictive Immune-Related Gene Signature Associated With Hepatocellular Carcinoma Patient Prognosis

“… 4 Different treatments are selected for HCC patients including resection, ablation, hepatic transplantation, transarterial chemoembolization or transarterial radioembolization, systemic treatment, or palliative care as per the Barcelona Clinic Liver Cancer. 5 , 6 As it can eliminate any underlying disease while maintaining organ function, hepatic transplantation is the optimal treatment for HCC patients. 7 , 8 However, the number of livers available for transplantation is limited, and this treatment can be expensive and associated with risks of immune-mediated transplant rejection.…”