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Hepatic stem cells and transforming growth factor β in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. It arises from modulation of multiple genes by mutations, epigenetic regulation, noncoding RNAs and translational modifications of encoded proteins. Although >40% of HCCs are clonal and thought to arise from cancer stem cells (CSCs), the precise identification and mechanisms of CSC formation remain poorly understood. A functional role of transforming growth factor (TGF)-β signalling in liver and intestinal stem cell niches has been demonstrated through mouse genetics. These studies demonstrate that loss of TGF-β signalling yields a phenotype similar to a human CSC disorder, Beckwith–Wiedemann syndrome. Insights into this powerful pathway will be vital for developing new therapeutics in cancer. Current clinical approaches are aimed at establishing novel cancer drugs that target activated pathways when the TGF-β tumour suppressor pathway is lost, and TGF-β itself could potentially be targeted in metastases. Studies delineating key functional pathways in HCC and CSC formation could be important in preventing this disease and could lead to simple treatment strategies; for example, use of vitamin D might be effective when the TGF-β pathway is lost or when wnt signalling is activated.

Key Points

  • Hepatocellular carcinoma (HCC) is a common and lethal cancer; its incidence is expected to increase over the next 20 years

  • Worldwide, HCC is the fifth most commonly occurring cancer and the third most common cause of cancer-related deaths

  • Around 40% of liver cancers are clonal and could arise from cancer stem cells (CSCs)

  • Multiple pathways, including the transforming growth factor (TGF)-β tumour suppressor pathway, are involved in the generation of CSCs

  • Genetic studies demonstrate the protective role of the TGF-β pathway, and focused research is giving unique insight into new treatment strategies

  • Future therapies that target CSCs are likely to be beneficial

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Figure 1: Effect of loss of TGF-β signalling in the development of hepatocellular carcinoma.
Figure 2: Developing treatment strategies in HCC from bench to bedside.
Figure 3: The TGF-β signalling pathway.
Figure 4: TGF-β pathway proteins β-II spectrin and SMAD3 are involved in hepatocarcinogenesis.

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Acknowledgements

We thank Beth Allen and Wilma Jogunoori for critical review of the manuscript. L. Mishra's work was supported by National Institutes of Health RO1-CA106614, RO1-CA042857, PO1-CA130821, RC2-AA019392, R. Robert and Sally D. Funderburg Research Scholar, the Ben Orr Award, and P30-CA016672, P30-DK56338 and P. Farci's work is supported by the Intramural Research Program of the National Institutes of Health and National Institute of Allergy and Infectious Diseases.

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Majumdar, A., Curley, S., Wu, X. et al. Hepatic stem cells and transforming growth factor β in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 9, 530–538 (2012). https://doi.org/10.1038/nrgastro.2012.114

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