Liver Stem Cells and Molecular Signaling Pathways in Hepatocellular Carcinoma

摘要

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-β/TBR), insulin-like growth factor/IGF-1 receptor (IGF/IGF-1R), hepatocyte growth factor (HGF/MET), Wnt/β-catenin/FZD, and transforming growth factor-α/epidermal growth factor receptor (TGF-α/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. Hepatocellular carcinoma (HCC) is the fifth most common solid malignancy worldwide and causes more than 600,000 deaths annually. 1 Current data indicate that the incidence of HCC is steadily increasing in the United States. 2 , 3 Prognosis remains extremely poor with a 5-year survival rate of less than 5% without treatment. 3 Currently, the only curative therapeutic option for early-stage HCC is surgical intervention, including percutaneous ablation, hepatic resection, and liver transplantation. However, only 12% of diagnosed HCC patients are deemed eligible for curative therapy. 4 , 5 Accumulating evidence suggests that development of HCC is a multistep process associated with changes in host gene expression, altered DNA methylation, and point mutations or loss of heterozygosity (LOH) in selected cellular genes. 6 The dynamics of these cellular changes remain unclear, and it is still a challenge to identify the rate-limiting steps in initiation and progression of HCC. However, a number of molecular changes occur in high frequency in preneoplastic tissues, such as cirrhotic tissue, hepatic adenomas and dysplastic nodules. For example, chronic hepatitis B virus (HBV) infection, which is one of the most prominent risk factors for hepatocarcinogenesis, appears to disrupt senescence-related pathways by different mechanisms. These include inactivation of p53, p55 sen and hyperphosphorylation of the retinoblastoma protein (pRb), as well as down-regulation of sui1 (a translational factor) and the cyclin-dependent kinase inhibitor, p21WAF1/CIP1/SDI1. 7 – 9 Perturbation of several signaling pathways such as wingless (Wnt/β-catenin/FZD), JAK/STAT, MAPK, insulin-like growth factor 2 (IGF-2), and transforming growth factor-beta (TGF-β) have also been identified. 10 Approximately 40% of HCCs display chromosomal abnormalities. 11 – 14 In addition, microsatellite instability (MSI) and dysfunction of the mismatch repair genes, hMSH2 and hMLH1, are present in up to 11% of HCCs. 15 , 16 These are in turn associated with mutations in TGFβRII, M6P/IGFIIR, and BAX genes. 17 Among proto-oncogenes, c-myc is upregulated in approximately 50% of HCCs, 18 , 19 and cyclin D1 is overexpressed in approximately 40% of HCCs. 20 , 21 Dysregulation of these positive mediators of cellular proliferation promotes autonomous and unregulated cellular growth in HCC.