Liver Regeneration and Carcinogenesis: Molecular and Cellular Mechanisms

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There are two events in which the liver has the capability to regenerate, one being a partial hepatectomy and the other being damage to the liver by toxins or infection 1. The processes described below deal with the pathways triggered after a partial hepatectomy.

Correlation of Liver Growth and Function During Liver Regeneration and Hepatocarcinogenesis

Following the event of partial hepatectomy, there are three phases for the process of regeneration. The first phase is the priming phase and during this portion, hundreds of genes are activated and prepare the liver for regeneration.

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This priming phase occurs within hours after the hepatectomy and deals mainly with events prior to entering the cell cycle and ensuring that hepatocytes can maintain their homeostatic functions. These two factors are major components of liver regeneration. Immediately after a hepatectomy, there is an activation of numerous signaling pathways that start the process of regeneration.

The first being an increase in urokinase activity. Urokinase is known to activate matrix remodeling. This remodeling causes the release of HGF hepatic growth factor and from this release now c-Met can also be activated. EGFR is also activated in the same way as c-Met, and these two growth factors play a major role in the regeneration process. These processes occur outside of the hepatocyte and prime the liver for regeneration.

This process is able to bring the hepatocytes back into their quiescent state. Sometimes, hepatocytes do not have the ability to proliferate and an alternative form of regeneration is able to take place to rebuild the liver. This can happen with the help of biliary epithelial cells having the capability of turning into hepatocytes when the original hepatocytes have problems proliferating.

The same also occurs vice versa, with hepatocytes being able to turn into biliary cells when they cannot proliferate. Both of these kinds of cells are facultative stem cells for each other. This results in activation of key signaling pathways such as the p38 mitogen-activated protein kinase and nuclear factor kappa B pathways, leading to upregulation of genes involved in cytokine production and subsequent inflammation, alterations in apoptotic pathways, and tumor formation [ 7 ].

Interestingly, HCV infection has also been found to induce insulin resistance IR , which in turn has been closely linked to the development of fibrosis and type 2 diabetes in these patients [ 29 ]. Although the mechanisms involved in the development of IR are not fully understood, the immune response against HCV infection is thought to be involved and research suggests that the process may be multifactorial.

These proinflammatory cytokines are both known to induce IR [ 32 ], and there is evidence to suggest that Kupffer cells [ 7 ] stimulated by oxidative stress [ 33 ] and exposure to the HCV core protein [ 34 ] are a likely source. Taken together, these data suggest that the process by which HCV infection can contribute to IR is complex and involves multiple mechanisms.

Patients with both HCV infection and alcohol abuse have been shown to develop more severe fibrosis and have higher rates of cirrhosis and HCC than nondrinkers [ 35 ]. The risk for developing HCC has also been shown to increase as levels of alcohol intake rise [ 28 ]. The mechanisms by which alcohol worsens HCV-related liver disease are not clear, although several possibilities have been proposed, including: greater HCV replication in the presence of alcohol; alcohol-associated changes in the hypervariable region of the viral genome, leading to more aggressive HCV-related liver disease and resistance to interferon therapy; and inhibition of hepatic expression of Bcl-2 by alcohol, resulting in increased apoptosis and more severe liver injury [ 35 ].

However, the dominant mechanism for synergism between alcohol and HCV infection appears to be increased oxidative stress. As mentioned above, HCV core protein localizes at the mitochondrial membrane and promotes oxidative stress. Ethanol potentiates this mitochondrial injury by further increasing reactive oxygen species ROS production and enhancing hepatic glutathione oxidation.

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Autoimmune hepatitis AIH is a condition of unknown etiology that is characterized by a progressive destruction of the liver parenchyma, often leading to fibrosis and liver cirrhosis. This surprisingly low incidence of HCC in patients with AIH suggests that there may be some pathologic mechanism preventing cancer progression. One hypothesis has highlighted the common use of immunosuppressants in these patients. If confirmed, this could affect future therapeutic options afforded to patients with HCC.

However, further characterization is needed before any definitive conclusions can be drawn. It occurs in the absence of alcohol use, although the hepatic histology appears consistent with alcoholic hepatitis [ 42 ], with changes in histology including hepatic steatosis, inflammation, hepatocyte injury as exemplified by cytologic ballooning and Mallory's hyaline, and fibrosis [ 43 ].

Epidemiologic studies show that NAFLD is closely linked with the metabolic syndrome, particularly type 2 diabetes mellitus and obesity [ 45 ], with NAFLD occurring almost universally among diabetic patients who are morbidly obese [ 46 ]. Moreover, NASH in association with multiple components of the metabolic syndrome is thought to increase the risk for developing chronic liver disease, cirrhosis, and HCC [ 45 ]. Although the pathophysiologic mechanisms driving NAFLD and the associated progressive hepatocellular damage are not fully understood, a number of processes have been described.

IR is a complex process that likely involves both insulin secretion and action, and is closely associated with obesity [ 46 ].

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IR causes increased peripheral lipolysis and increases circulating fatty acids that are taken up by the liver. At the same time, there is an increase in de novo liponeogenesis in the hepatocytes and a reduction in the hepatic secretion of very-low-density lipoproteins, resulting in hepatic triglyceride accumulation or fatty liver. Insulin resistance and the development of non-alcoholic steatohepatitis [ 46 ].

Nonalcoholic fatty liver disease. CMAJ ;— Reproduced with permission from Professor Keith Lindor. Increased intrahepatic fatty acid levels are also thought to provide a source of oxidative stress, which may play an important role in the development from steatosis to steatohepatitis associated with progression to cirrhosis [ 48 ]. ROS produced by the mitochondria oxidize fat deposits to release lipid peroxidation products, which together with ROS impair the respiratory chain via oxidative damage to the mitochondrial genome [ 49 ].

Proinflammatory cytokines also activate hepatic stellate cells, which produce a collagen matrix and drive the development of fibrosis [ 9 ]. HCC in noncirrhotic livers is rare and mostly occurs as a result of HBV infection, as described earlier [ 2 ]. However, HCC in noncirrhotic livers can also occur as a result of contamination of foodstuffs with aflatoxin B1 [ 50 ].

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Aflatoxin B1 is a mycotoxin produced by the Aspergillus fungus that grows readily on food when stored in warm, damp conditions [ 2 ]. When ingested, it is metabolized into the active AFB 1 -exo- 8,9-epoxide, which binds to DNA to cause damage, including the production of mutations of the p53 tumor suppressor gene. Another risk factor for developing HCC is alcoholic liver disease.

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As mentioned, heavy alcohol intake is thought to act synergistically with HCV to promote liver cirrhosis [ 28 ]. Finally, a number of other risk factors for developing HCC exist, including primary biliary cirrhosis, silent chronic liver disease, and hereditary hemochromatosis [ 52 ]. Other less common causes of hepatic cirrhosis that could contribute to the development of HCC are shown in Table 2 and include genetic metabolic diseases, certain infections, and vascular and venous abnormalities. Infectious agents such as brucellosis, syphilis, echinococcosis, and schistosomiases are known to cause cirrhosis, as are vascular abnormalities such as right-sided heart failure, pericarditis, hereditary hemorrhagic telangiectasia, and veno-occlusive diseases, for example, Budd-Chiari syndrome [ 52 , 53 ].

Liver Regeneration and Carcinogenesis

Common causes of liver cirrhosis that could result in the development of hepatocellular carcinoma [ 52 ]. Given the established links between liver cirrhosis and the development of HCC, there is a strong rationale for surveillance of patients with cirrhosis, and guidelines support observation of this group, regardless of etiology. In contrast, in the U. Furthermore, studies in China and Italy have shown that survival is improved by surveillance for HCC [ 55 , 56 ].

Earlier diagnosis of HCC significantly affects treatment choices [ 54 , 57 — 60 ] and treatment recommendations for patients with earlier-stage HCC are described in detail elsewhere in this issue [ 61 ]. That study showed that all screened patients were diagnosed with earlier-stage disease and were 10 times more likely to have received potentially curative treatment than unscreened patients [ 62 ]. Ultrasound is a widely used method of detecting HCC, although it has been suggested that the reliability of this method is influenced by the expertise of the operator as well as the provision of dedicated equipment [ 54 ].

Combining ultrasound and AFP appears to improve detection rates, but also increases costs and the rate of false positives. The American Association for the Study of Liver Diseases guidelines recommend that surveillance for HCC be performed using ultrasonography at 6- to month intervals and that AFP alone should not be used for screening unless ultrasound is not available [ 59 ].

Currently, the presence of cirrhosis is the key factor that influences the decision to implement surveillance, irrespective of the etiology of the liver disease. However, guidelines also support surveillance for HCC in specific groups of individuals with HBV, even without cirrhosis e. The complex etiology of HCC affects the possible treatment options offered to patients.

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For example, patients with compromised liver function as a result of cirrhosis are ineligible for surgical resection because of the risk for postoperative decompensation [ 54 ]. The coexistence of cirrhosis and associated liver dysfunction may also limit the nonsurgical treatment options available and is likely to be a large contributory factor to the poor prognosis of many HCC patients. The presence of comorbidities such as cardiac conditions or neurodegenerative disorders in patients with hemochromatosis, or diabetes, obesity, or cardiac conditions in patients with NASH, may influence treatment options for HCC, and the use of concomitant medications should also be carefully considered.