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.

Figure 1

Effect of loss of TGF-β signalling in the development of hepatocellular carcinoma. Induction of cellular changes through loss of TGF-β, such as SMAD linker phosphorylation and loss of β-II spectrin and SMAD proteins, can lead to development of hepatocellular carcinoma.

Figure 2

Developing treatment strategies in HCC from bench to bedside. Loss of TGF-β signalling results in HCC. Approaches to identifying appropriate targets and the pathways activated when TGF-β signalling is lost (for example, IL-6–STAT3) have yielded few promising leads for drug development in HCC. Vitamin D, Keap1 inhibitor RTA 402, PARP and HDAC inhibitors are currently in clinical trials. Identification of biomarkers based on genome-wide association studies has been another avenue of research and has revealed molecules that could in future be monitored during the progression of HCC. Abbreviations: GWAS, genome-wide association studies; HCC, hepatocellular carcinoma; HDAC, histone deacetylase; PARP, and poly-ADP-ribose polymerase; SNP, single nucleotide polymorphism; TGF-β, transforming growth factor β; TGFR-2, TGF-β receptor 2.

Figure 3

The TGF-β signalling pathway. This pathway is initiated by a TGF-β signal, which activates TGFR-2 that in turn activates TGFR-1. The adaptor protein β-II spectrin is phosphorylated by TGFR-1 and recruits SMAD proteins to the receptor. The tumour suppressor SMAD4, becomes associated with SMAD homologues after they are phosphorylated, and a complex, made up of SMAD3, SMAD4, and phosphorylated β-II spectrin, is created to maintain signalling that fosters the normal growth of cells. The RBX1–SCF(BTRC) complex regulates the proteosomal degradation of SMAD3 by polyubiquitination. Praja1 is responsible for the proteosomal degradation of β-II spectrin. This occurs after specific genes, including CDKN1A (also known as p21), CDKN2B (also known as p15), PAI1, and CDH1 have been activated by SMAD complexes. In HCC, as in almost all gastrointestinal cancers, the TGF-β pathway is inactivated. NRF2 induces the expression of cytoprotective genes and is inhibited by KEAP1, which is associated with an increase in tumour cell migration. KEAP1 forms a complex with CUL3–RBX1, which then polyubiquitinates NRF2, thereby targeting it for proteosomal degradation. The novel triterpenoid RTA 402 (which is now in clinical trials for the treatment of HCC) inhibits KEAP1 and Praja1 and thereby exerts its antitumour activity. Abbreviations: HCC, hepatocellular carcinoma; SBE, SMAD binding element; TGF-β, transforming growth factor β; TGFR, TGF-β receptor.

Figure 4

TGF-β pathway proteins β-II spectrin and SMAD3 are involved in hepatocarcinogenesis. a | Schematic diagram of liver cancer development showing a role for the lack of TGF-β signalling in different stages during hepatocarcinogenesis. b | Liver samples from wild-type and c | β2SP^+/− mice treated with alcohol were stained with Masson trichrome. Significant steatosis (arrowhead) and fibrosis (arrow) are seen in the β2SP^+/− mice. d | HCC in β2SP^+/− and e | β2SP^+/−Smad3^+/− mice. These mice exhibit an increased prevalence of HCC (arrows) and gastrointestinal cancers and share many phenotypic characteristics observed in patients with Beckwith–Wiedemann syndrome, a hereditary cancer stem cell syndrome. Abbreviations: HCC, hepatocellular carcinoma; TGF-β, transforming growth factor β. Part d reproduced with permission from Nature Publishing Group © Katuri, V. et al. Oncogene 25, 1871–1886 (2006).