Liver stem cells and molecular signaling pathways in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Surgical intervention is the only curative option, with only a small fraction of patients being eligible. Conventional chemotherapy and radiotherapy have not been effective in treating this disease, thus leaving patients with an extremely poor prognosis. In viral, alcoholic, and other chronic hepatitis, it has been shown that there is an activation of the progenitor/stem cell population, which has been found to reside in the canals of Hering. In fact, the degree of inflammation and the disease stage have been correlated with the degree of activation. Dysregulation of key regulatory signaling pathways such as transforming growth factor-beta/transforming growth factor-beta receptor (TGF-beta/TBR), insulin-like growth factor/IGF-1 receptor (IGF/IGF-1R), hepatocyte growth factor (HGF/MET), Wnt/beta-catenin/FZD, and transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) in this progenitor/stem cell population could give rise to HCC. Further understanding of these key signaling pathways and the molecular and genetic alterations associated with HCC could provide major advances in new therapeutic and diagnostic modalities.

Figure 1.

Schematic representation of fetal liver development and hepatocarcinogenesis process based on stem cell model. About half of the small cell dysplasic lesions consist of progenitor cells and intermediate cells. Abbreviations: AFP = alpha-fetoprotein; Alb = albumin; HCC = hepatocellular carcinoma.

Figure 2.

Transforming growth factor-beta (TGF-β) signals through distinct receptors and Smads, which are modulated by β-spectrin embryonic liver fodrin protein (ELF). TGF-β binds to serine/threonine kinase receptor complexes I and II (TBRI and TBRII), which subsequently phosphorylates receptor-associated Smad proteins, such as Smad2 and Smad3. Smad2/3 then forms heterometric complex with Smad4 and ELF proteins and translocates to the nucleus, interacting with transcriptional factor and activating target genes. Abbreviation: SBE = Smad binding element.

Figure 3.

In the absence of Wnt stimulation, the APC (adenomatous polyposis coli) forms a trimeric complex, known as the “destruction complex,” with glycogen synthase kinase-3β (GSK) and Axin. This complex then interacts with β-catenin and degrades by the ubiquitin-proteasome pathway. When Wnt ligands bind to the seven-transmembrane receptor, the cytoplasmic protein Dishevelled (Dsh) is recruited to the membrane and binds to Axin1 and Axin2. The mechanism of Dsh-mediated inhibition of Axin is not well understood, but it has been suggested that Dsh might disrupt the destruction complex. Inhibition of Axin results in accumulation of β-catenin, which subsequently translocates into the nucleus. β-catenin interacts with LEF/TCF (lymphocyte enhancer factor/T cell factor) proteins and serves as a coactivator of LEF/TCFs to stimulate transcription of Wnt target gene. Grouch protein (Gro) acts as corepressor of LEF/TCFs and normally binds to LEF/TCFs in the absence of β-catenin. New therapeutic treatments aimed at this pathway include monoclonal antibodies, cyclooxygenase (COX)-2 inhibitors, and several small molecules.

Figure 4.

Simplified schematic diagram of insulin-like growth factor (IGF) signaling. IGF-I and IGF-II bind to IGF receptor (IGFR), a receptor tyrosine kinase (RTK), with high affinity resulting in phosphorylation of intracellular proteins including insulin receptor substrate (IRS). The signal is then conveyed to specific downstream effectors such as phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT/PKB), and mitogen-activated protein kinase (MAPK) pathways. These pathways play crucial roles in antiapoptosis as well as cell proliferation. Bioavailability of both IGFs is influenced by the presence of IGF binding proteins (IGFBP). New therapeutic agents such as AG1024 and gefitinib aim to block this signaling pathway at level of the receptor. Downstream targeting agents such as rapamycin, CCI-779, and RAD001 are also under investigation.

Figure 5.

Simplified schematic of hepatocyte growth factor (HGF)/MET signaling pathway. Activation of phosphorylation of the kinase domain in cMET, a receptor tyrosine kinase (RTK), by HGF results in activation of adaptor proteins: growth factor receptor-bound protein2 (Grb2) and Grb2-associated binding protein (Grb2 and Gab1). Activation of these adaptor proteins leads to activation of various downstream effectors resulting in transcription of various genes important in mitogenesis, angiogenesis, and morphogenesis.

Figure 6.

Simplified schematic diagram of transforming growth factor-alpha/epidermal growth factor receptor signaling pathway (TGF-α/EGFR). TGF-α binding to EGFR results in stimulation of the endogenous receptor tyrosine kinase (RTK). The activated membrane-bound EGFR serves as a docking site for recruitment of proteins such as Src homology 2 domain containing (Shc) and growth factor receptor-bound protein2 (Grb2). The signal then activates one of several intracellular signal transduction pathways including protein kinase A (PKA), mitogen-activated protein kinase (MAPK), Jak/Stat, and C-src pathways, which play important roles in cell proliferation. New therapeutic agents such as erlotinib, cetuximab, and lapatinib aim to block this signaling cascade.