Cyclooxygenases in hepatocellular carcinoma

Many epidemiological studies demonstrate that treatment with non-steroidal anti-inflammatory drugs （NSAIDs） reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase （COX） enzymes are well-known targets of NSAIDs. However, conventional NSAIDs nonselectively inhibit both the constitutive form COX-1, and the inducible form COX-2. Recent evidence indicates that COX-2 is an important molecular target for anticancer therapies. Its expression is undetectable in most normal tissues, and is highly induced by proinflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, malignant, and metastastic cancers, including hepatocellular carcinoma （HCC）. Overexpression of COX-2 in patients with HCC is generally higher in welldifferentiated HCCs compared with less-differentiated HCCs or histologically normal liver, suggesting that COX-2 may be involved in the early stages of hepatocarcinogenesis, and increased expression of COX-2 in noncancerous liver tissue has been significantly associated with shorter disease-free survival in patients with HCC. In tumors, overexpression of COX-2 leads to an increase in prostaglandin （PG） levels, which affect many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness and metastatic potential of tumor cells. The availability of novel agents that selectively inhibit COX-2 （COXIB）, has contributed to shedding light on the role of this molecule. Experimental studies on animal models of liver cancer have shown that NSAIDs, including both selective and non-selective COX-2 inhibitors, exert chemopreventive as well as therapeutic effects. However, the key mechanism by which COX-2 inhibitors affect HCC cell growth is as yet not fully understood. Increasing evidence suggests the involvement of molecular targets other than COX-2 in the antiproliferative effects of COX-2 selective inhibitors. Therefore, COX-inhibitors may use both COX-2- dependent and COX-2-independent mechanisms to mediate their antitumor properties, although their relative contributions toward the in vivo effects remain less clear. Here we review the features of COX enzymes, the role of the expression of COX isoforms in hepatocarcinogenesis and the mechanisms by which they may contribute to HCC growth, the pharmacological properties of COX-2 selective inhibitors, the antitumor effects of COX inhibitors, and the rationale and feasibility of COX-2 inhibitors for the treatment of HCC.

Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma: Possible role in tumor promotion and angiogenesis

AIM： To investigate the association of cyclooxygenase-2 （COX-2） expression with angiogenesis and the number and type of inflammatory cells （macrophages/Kupffer cells; mast cells） within primary hepatocellular carcinoma （HCC） tissues and adjacent non-tumorous （NT） tissues. METHODS： Immunohistochemistry for COX-2, CD34, CD68 and mast cell tryptase （MCT） was performed on 14 well-characterized series of liver-cirrhosis-associated HCC patients. COX-2 expression and the number of inflammatory cells in tumor lesions and surrounding liver tissues of each specimen were compared. Moreover, COX-2, CD34 staining and the number of inflammatory cells in areas with different histological degrees within each tumor sample were comparatively analyzed. RESULTS： The percentage of COX-2 positive cells was significantly higher in NT tissues than in tumors. COX-2 expression was higher in well-differentiated HCC than in poorly-differentiated tissues. Few mast cells were observed within the tumor mass, whereas a higher number was observed in the surrounding tissue, especially in peri-portal spaces of NT tissues. Abundant macrophages/ Kupffer cells were observed in NT tissues, whereas the number of cells was significantly lower in the tumor mass. However, a higher cell number was observed in the welldifferentiated tumor and progressively decreased in relation to the differentiation grade. Within the tumor, a positive correlation was found between COX-2 expression and the number of macrophages/Kupffer cells and mastcells. Moreover, there was a positive correlation between CD34 and COX-2 expression in tumor tissues. Comparison between well- and poorly-differentiated HCC showed that the number of CD34-positive cells decreased with dedifferentiation. However, COX-2 was the only independent variable showing a positive correlation with CD34 in a multivariate analysis. CONCLUSION： The presence of inflammatory cells and COX-2 expression in liver tumor suggests a possible relationship with tumor angiogenesis. COX-2 expressing cells and the number of macrophages/Kupffer cells and mast cells decrease with progression of the disease.

Non invasive tools for the diagnosis of liver cirrhosis

Liver cirrhosis(LC),the end stage of many forms of chronic hepatitis of different etiologies is a diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules surrounded by annular fibrosis.This chronic progressive clinical condition,leads to liver cell failure and portal hypertension,which can favour the onset of hepatocellular carcinoma.Defining the phase of the natural history is crucial for therapeutic choice and prognosis.Liver biopsy is currently considered the best available standard of reference but it has some limits,so alternative tools have been developed to substitute liver biopsy when assessing liver fibrosis.Serum markers offer a cost-effective alternative to liver biopsy being less invasive and theoretically without complications.They can be classified into direct and indirect markers which may be used alone or in combination to produce composite scores.Diagnostic imaging includes a number of instruments and techniques to estimate liver fibrosis and cirrhosis like ultrasound(US),US Doppler,contrast enhanced US andElastography.US could be used for the diagnosis of advanced LC while is not able to evaluate progression of fibrosis,in this case Elastography is more reliable.This review aims to revise the most recent data from the literature about non invasive methods useful in defining liver fibrosis.

Nanotechnology applications for the therapy of liver fibrosis

Chronic liver diseases represent a major global health problem both for their high prevalence worldwide and,in the more advanced stages,for the limited available curative treatment options.In fact,when lesions of different etiologies chronically affect the liver,triggering the fibrogenesis mechanisms,damage has already occurred and the progression of fibrosis will have a major clinical impact entailing severe complications,expensive treatments and death in end-stage liver disease.Despite significant advances in the understanding of the mechanisms of liver fibrinogenesis,the drugs used in liver fibrosis treatment still have a limited therapeutic effect.Many drugs showing potent antifibrotic activities in vitro often exhibit only minor effects in vivo because insufficient concentrations accumulate around the target cell and adverse effects result as other non-target cells are affected.Hepatic stellate cells play a critical role in liver fibrogenesis,thus they are the target cells of antifibrotic therapy.The application of nanoparticles has emerged as a rapidly evolving area for the safe delivery of various therapeutic agents(including drugs and nucleic acid)in the treatment of various pathologies,including liver disease.In this review,we give an overview of the various nanotechnology approaches used in the treatment of liver fibrosis.