Molecular Aspects of Hepatocellular Carcinoma

Hepatocellular Carcinoma (HCC) is one of the commonest solid organ tumors worldwide. Based on WHO data, HCC is the fifth most common malignancy in men and the ninth in women, accounting for approximately 5.6% of all human cancers [1]. Furthermore, HCC is rapidly fatal in the majority of patients, which makes its mortality nearly 100%. The majority of patients with HCC have underlying liver disease [2], therefore, HCC is regarded as a serious complication of chronic liver diseases, especially advanced liver fibrosis and/or cirrhosis. Not surprisingly, the incidence of HCC is linked closely to the prevalence of major causes of liver fibrosis and cirrhosis, such as chronic viral hepatitis and excessive alcohol consumption [3, 4]. In this article，we will give a brief overview on the intimate relationship between liver fibrosis and HCC.

The evidence for a possible link between Non-alcoholic steatohepatitis (NASH) and Hepatocellular carcinoma (HCC) is clearly emerging. A significant proportion of HCC cases develop in cryptogenic cirrhosis, which is associated with obesity and diabetes, main risk factors for NASH. In longitudinal studies, HCC appears to be a rare and long-term complication of NASH, with a prevalence ranging from 0%-2.8% over 20 years. However, once cirrhosis had developed 4%-27% of cases can be complicated by HCC. Diagnostic delay as well as the older age and the concurrent presence of severe metabolic or vascular disease are often a contraindication for a potentially curative treatment such as OLT. Careful screening and surveillance for HCC in NASH patients is mandatory, but limited by the insidious course of the disease and the lack of reliable, non-invasive diagnostic tools. The development of HCC probably stems from the contribution of cirrhosis and of the metabolic derangements associated with NASH. Diabetes and obesity have been established as independent risk factors for HCC. Insulin resistance, oxidative stress and an imbalance in adipokine/cytokine interplay, involved in the development of NASH, could also stimulate liver carcinogenesis. The future prevalence of HCC in NASH and in NASH-related cirrhosis is expected to increase with the growing epidemic of diabetes and obesity. A potential role of pharmacological therapy can be envisaged, but currently our main efforts should be directed to promote healthful dietary practices and physical activity as a cultural norm.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the commonest viral causes of hepatocellular carcinoma (HCC) globally. Hepatitis B virus can integrate into the human genome and influences the carcinogenesis by cis- and trans-activation mechanisms on top of necroinflammation and liver fibrosis/cirrhosis. Various virological factors including high viral load, genotype C HBV and basal core promoter mutations have been described to associate with increased risk of HCC. On the other hand, HCV will not integrate into the host genome. HCV contributes to hepatocarcinogenesis predominantly through hepatic necroinflammation and liver cirrhosis, but it may also alter lipid metabolism and signal transduction pathways via its structural and nonstructural proteins. Although HCV genotype and HCV RNA level do not influence the rate of fibrosis progression or the risk of HCC development, treatment of HCV infection can improve liver fibrosis/cirrhosis and the subsequent risk of HCC.

Although the exact etiology and mechanisms of hepatocellular carcinoma (HCC) are not clear, a few risk factors have been identified. Liver cirrhosis, which is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury, is a major risk factor for HCC. In the cirrhotic liver, normal blood flow is impaired, and the ability of the liver to detoxify exogenous carcinogens or endogenous metabolites is compromised, thus increasing the chance of carcinogenesis. Cirrhosis has a multifactorial etiology, which vary with geographic regions. In Western countries, cirrhosis is mainly the result of chronic hepatitis C infection and alcohol abuse. In contrast, in most parts of Asia and sub-Saharan Africa, hepatitis B is the leading cause of cirrhosis. Except for virus infection, there are many non-viral causes of liver cirrhosis, including but not limited to nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cirrhosis, and hereditary diseases. In some cases, no clear etiology could be found (cryptogenic cirrhosis). However, the incidence of HCC varies greatly with etiologies and the molecular mechanisms linking cirrhosis and HCC are not well defined. In this article, the authors aim to review the evidences supporting (or against if any) the role of nor-viral causes in the development of HCC and discuss how non-virus factors promote HCC formation.

Hepatocellular carcinoma (HCC) is one of the major health problems worldwide. It was recently reported that systemic treatment with sorafenib, a multiple kinase inhibitor, for advanced HCC patients with mild hepatic impairment (Child-Pugh class A) significantly extends overall survival. These results highlight the importance of understanding the molecular pathways to hepatocarcinogenesis that can lead to improvement in treatment for unresectable HCC. In this article, we provide an update on the molecular pathways to hepatocarcinogenesis, focusing on the extracellular signal-regulated kinase [Erk: mitogen activated protein kinase (MAPK)], Wnt/β-catenin, apoptosis, transforming growth factor-beta (TGF-β), phosphoinositide-3-kinase (PI3K)/Akt, mammalian target of rapamycin (mTOR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Hedgehog, p53, cytokine and sex steroid pathways. Molecular targeted therapy against these pathways will shed new light on the treatment of advanced HCC patients.

Hepatocellular carcinoma (HCC) is a highly malignant tumor that often follows an aggressive clinical course. Consequently, the 5-year survival of most patients remains low. Despite the growing knowledge of HCC tumor biology, the transcriptional regulation of many causative tumor suppressors or oncogenes remains unclear. MicroRNAs (miRNAs) have emerged as key posttranscriptional regulators of genes expression. Although the miRNA family represents only a minor fraction of the genome, they hold vital importance in diverse physiological and pathological processes, including cell survival, differentiation, responses to external stress and morphogenesis. It is also apparent that specific miRNAs can contribute to cellular transformation and tumorigenesis through their influence on the protein translation of multiple cancer-related genes. Recent studies further ascribe causative links between miRNA dysregulations and HCC oncogenesis. An understanding on the molecular mechanisms by which miRNAs regulate HCC development may provide new avenues of research that could aid in the early diagnosis and treatment of this highly aggressive tumor. In this review, we briefly discuss how miRNAs can act as oncogenes and tumor suppressors in HCC, and discuss the miRNAs that potentially govern important cancer-related pathways.

There is accumulating evidence to suggest an important role of liver stem/progenitor cells in thedevelopment of hepatocellular carcinoma. This review summarizes the available evidence for a link between liver stem cells and hepatoma and focuses on two processes that are consistently associated with chronic liver damage, which often culminates in liver cancer; namely inflammation and apoptosis. This review gleans evidence from the literature, which supports the view that early changes are initiated and sustained by the inflammatory environment that follows damage. In the context of liver disease, these can be chemicals (such as alcohol) or viruses (mainly HBV and HCV). Then progression of the carcinogenic process is facilitated by continued cell proliferation mediated by inflammatory cytokines. This involves selection of the fittest cells that are best able to resist the hostile environment, which the damaging agent produces, as well as the inflammatory milieu. The fittest cells are those best able to resist cell death signals. As these notions are well-defined in hematopoietic stem cells, they are discussed. Little is known of these signals in liver stem/progenitor cells but new data is emerging, which is summarized. The availability of mouse models, which provided much of the data on hemopoietic cells will greatly assist efforts to determine the role of apoptotic pathways in liver cancer stem cells.

The world population is aging, meanwhile, the incidence and the mortality of the hepatocellular carcinoma are increasing year by year. The peak age of onset of HCC varies with the geographical locations. More than 40 years ago, the question "was there a relationship between carcinogenesis and aging?" was posed. Clinical research and epidemiological data gathered over the past few decades have suggested that process of aging must have played some role on the development of hepatocellular carcinoma. Understanding the mechanism of aging and its role in liver cancer is practically important in the prevention, early diagnosis, treatment, and prediction of prognosis. However, the molecular mechanisms by which aging predisposes hepatocarcinogenesis is largely unknown. In this chapter, we aim to review the possible molecular mechanisms of how aging might have promoted hepatic carcinogenesis.

Cancer metastasis is a highly complex event involving the generation of new blood and lymph vessels, growth, invasion with breakdown and crosstalk of the host matrix, escape from immune surveillance, transport to other sites with adhesion, and subsequent invasion of the organ that hosts the metastasis. Several participants in this tightly orchestrated procedure are important, for instance cell-adhesion molecules, signaling pathways, immune cells, enzymes and receptors, acting all in concert to guide the tumour cell to its new home. Looking at this complex network it becomes clear why therapeutic approaches are often disappointing and why there is still no cure for cancer. Further knowledge and research of the molecular mechanisms leading to this disastrous event are badly needed to find new therapeutic agents and to improve the quality of life and prognosis of patients with cancer. In this chapter we discuss the molecular mechanisms of liver cancer metastasis and their impact on discovering new biomarkers and therapeutic strategies.

The carcinogenesis of hepatocellular carcinoma (HCC) is a multifactorial and stepwise process. For efficient clinical management and curative treatment strategies, the early diagnosis of HCC is critical. In the follow-up of patients it is required to evaluate the efficacy of surgical, loco-regional and systemic therapies. For the evaluation of the disease, both diagnosis and follow-up of HCC, various imaging techniques, clinical scoring systems and biomarkers have been set into practice. The present overview intends to report on current biomarkers in liver tissue and serum and to discuss their applicability in HCC. Alpha-fetoprotein (AFP) and des- carboxy prothrombin (DCP or PIVKA II) serum levels in combination with imaging methods are currently used in most centers for the initial diagnosis and surveillance. Furthermore, novel markers as Glypican-3 or AFP-L3 in serum or liver tissue, circulating tumor cells, gene expression patterns and other molecular markers (circulating RNA, microRNA, methylation patterns of tumor related genes) are presented and discussed.

Hepatocellular carcinoma is the fifth most common cancer worldwide. Studies of the molecular mechanisms leading to hepatocarcinogenesis hold the key to improvements in diagnosis and treatment of this disease. Animal models give us the opportunity to study these mechanisms by manipulating the risk factors and associated genetic alterations that lead to hepatocarcinogenesis. Worldwide, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for more than two thirds of HCC cases. Therefore, HBV- and HCV-induced hepatocarcinogenesis in animals would most closely mimic the aetiology and possibly the associated pathogenesis of human HCC. Other risk factors include exposure to chemical carcinogens and other causes of cirrhosis. Rodents remain the most valuable animal models and can be classified as infection-associated, carcinogen-induced, and transgenic or inflammatory. From studies of these models, many potential molecular mechanisms have been identified as contributing to hepatocarcinogenesis, such as HBx, c-Myc, TGFα, IGF-II, H-ras, p53, NF-κB, and Wnt signaling pathways. Transgenic mouse models with the potential for wider use include the β-catenin/H-ras double transgenic mouse, the TGFα/c-Myc double transgenic mouse and the c-Met conditional knockout mouse (MetLivKO). These mice develop liver tumours with high penetrance and a short latency and pathological features similar to human HCC. Other species including rabbits, woodchucks, tree shrews, dogs, pigs and primates have been used to study diagnostic and therapeutic options in HCC. However, more work is required to unravel the sequence of events that leads to HCC in order to guide future prevention, diagnosis and treatment.

Prevention is the only realistic approach for reducing mortality rates associated with hepatocellular carcinoma (HCC). In this context, treatments which alter susceptibility to HCC or slow the progression of hepatitis to cirrhosis have been advocated to prevent or delay the appearance of HCC. Two controlled studies in Asia showed interferon and lamivudine to prevent or delay the onset of hepatitis B-related HCC, respectively. However, prevention of HCC by interferon and nucleos(t)ide analogues in hepatitis B virus (HBV) patients has been contradicted by several studies based on follow-up of patients with pharmacologically suppressed hepatitis B. Interferon trials demonstrated a moderate reduction of HCC risk in patients with chronic hepatitis C who achieved a sustained virological response, including cirrhotic patients. However, most studies were underpowered to capture enough hard end points of the natural history of hepatitis C, having preferentially enrolled patients with moderate liver impairment who have a better predicted compliance to interferon but a low risk of developing HCC. Evidence for tertiary prevention of HCC is still inconclusive, due to poor methodologies and scientific background of the studies.

Hepatocellular carcinoma (HCC) ranks the third most lethal cancer worldwide, and the incidence is continuously rising. HCC is resistant to conventional cytotoxic chemotherapy and radiotherapy, thus systemic chemotherapy is not an ideal option for patients with advanced HCC. With recent advances in the knowledge of hepatocarcinogenesis, there has been encouraging development in the systemic therapy for advanced HCC, particularly in the molecular targeted therapy of advanced HCC. Sorafenib, a multikinase inhibitor, has showed survival benefits in patients with advanced HCC. This advancement represents a breakthrough in the treatment of HCC. Bevacizumab, a molecule that targets the anti-angiogenic pathway and the Raf/mitogen-activated protein kinase pathways has also showed initial encouraging activity in treating advanced HCC. Currently, Sorafenib is the only agent that has been approved by FDA as a targeted therapy for patients with advanced HCC. Future progress seems likely to depend on using controlled clinical trials to explore the optimized synergistic treatment strategies, combined targeted therapy with surgical resection, liver transplantation, radiofrequency ablation and transcatheter arterial chemoembolization.

A pre-requisite for tumour growth and metastasis is angiogenesis, the sprouting and growth of new capillaries from pre-existing blood vessels. Tumours without the ability to induce the growth of new capillaries remain small, in the order of 1-2 mm3 [1]. Drugs are now available, such as Bevacizumab, to inhibit angiogenesis and human tumour growth. Hepatocellular carcinoma (HCC) is a very aggressive human cancer, has clear angiogenic characteristics and patients with HCC have a very poor clinical outlook. In this context, we review the mechanisms of the predominant angiogenic pathways and how their targeting can impact on liver tumour growth. We also discuss the role of hepatitis in influencing liver tumour blood vessel growth. Equally, the role of the hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is considered, since it is now one of most common causes of liver disease in Western Societies. There are links between angiogenesis and metabolism and although poorly researched in respect of HCC, these we examine as they may impact on liver tumour formation and progression. Finally, we report on the current status of trials of anti-angiogenic HCC therapy and consider the potential limitations of such a therapeutic strategy.

Hepatocellular carcinoma is a serious threat to global health. Surgery remains the best curative therapy but only a small number of patients may benefit. Non-surgical therapies are playing an increasingly important role for hepatocellular carcinoma. In this chapter, the authors aim to review the current non-surgical approaches to hepatocellular carcinoma, including transcatheter arterial (chemo) embolization, cryoablation, percutaneous ethanol injection, radiofrequency ablation, and interstitial laser coagulation, with a special emphasis on the molecular basis of these therapies. Understanding the underlying biological and molecular mechanisms of hepatocellular carcinoma will not only help surgeons to refine existing techniques, but may also help us develop novel therapeutic approaches.

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies worldwide, and it has the highest prevalence in Asia and Africa countries. Most symptomatic HCCs have a low surgical respectability and the disease usually progresses rapidly and has a very poor prognosis. The constant searching for the molecular and genetic mechanisms involved in the development of HCC is necessary for the development of more effective therapeutic strategies against this cancer. Over the last few years, many alternative approaches have been explored in the management of HCC. The possible therapeutic role of traditional Chinese medicine (TCM) against HCC has been extensively studied, and some showed promising results, but the underlying molecular mechanisms involved in the TCM against HCC remain largely unknown. In this review article, we aim to elucidate the possible molecular mechanisms of TCM in HCC therapy. Based on preliminary basic and clinical studies, TCM is able to induce apoptosis, inhibit cell proliferation, strengthen the host immune functions, and suppress the invasion and metastasis of HCC.

While thousands of randomized controlled trials (RCT) inform the treatment of many of the most lethal cancers, in hepatocellular carcinoma (HCC), only 77 RCT studies were published between 1978 and 2005. This systematic review sought to identify RCTs pertaining to the treatment of liver cancer published from January 2006 to July 2009 and evaluate their methodological quality. Thirty RCTs published in English were identified. Most (18) originated in Asia, one third in Europe and two were multi-country studies. A total of 4,139 patients were enrolled in these RCTs, for a mean of 138 patients per trial. 73% of these trials were of high methodological quality. The RCTs found that using monoclonal antibodies or gene therapy in conjunction with liver transplantation may extend transplant indications and that the use of interferon, lipiodol or adoptive immunotherapy in conjunction with liver resection may improve survival, but that this would need validation by larger studies. Radiofrequency ablation (RFA) is equally effective, and has fewer complications than liver resection. RFA is superior to percutaneous ethanol injection (PEI) for local disease control and combining RFA and PEI improves overall survival. The role of arterial occlusion during RFA awaits further validation. Transarterial chemoembolization (TACE) combined with RFA and immuno-modulators may warrant future exploration. Two large, high quality sorafenib trials confirmed the role of this agent in the systemic treatment of HCC. The octreotide trials have overall been disappointing, but benefits may exist for HCCs expressing somatostatin receptors. Although the last 4 years have witnessed significant progress in this field, the average of 9 RCTs per year for HCC treatment remains well behind the level of research activity in other cancers.

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