Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
Liver cancer stem cells (CSCs), a unique subset of hepatocellular carcinoma cells with stem cell features, dictate a hierarchical organization and contribute to treatment resistance and tumour recurrence.
Early studies using cell-sorting and xenotransplantation techniques identified various liver CSC markers that have laid important groundwork for current research in the field.
Lineage-tracing and cell-ablation studies in intact mouse tumours have provided insights into liver CSC plasticity, quiescence, renewal and treatment response.
Liver CSCs are capable of sustaining tumours by altering intrinsic regulators that converge into common signalling pathways.
Liver CSCs reside in dedicated niches where they interact reciprocally with cells and/or factors in the tumour microenvironment to regulate stemness.
Understanding the key traits and mechanisms of liver CSC survival provides opportunities to improve patient outcomes through improving prognostic models and therapeutic approaches.
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The authors regret omitting many reports from this Review owing to space constraints. The authors’ research was funded by the Research Grants Council of Hong Kong — Collaborative Research Fund (C7026-18G) as well as the ‘Laboratory for Synthetic Chemistry and Chemical Biology’ under the Health@InnoHK Program launched by Innovation and Technology Commission, The Government of Hong Kong Special Administration Region of the People’s Republic of China.
The authors declare no competing interests.
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Lee, T.KW., Guan, XY. & Ma, S. Cancer stem cells in hepatocellular carcinoma — from origin to clinical implications. Nat Rev Gastroenterol Hepatol 19, 26–44 (2022). https://doi.org/10.1038/s41575-021-00508-3
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