Progress Report
New frontiers in biomarkers for hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma represents the fifth most frequent cancer in the world; it commonly occurs on cirrhotic liver. Prognosis and survival are still poor, mainly because of diagnosis at a late stage and/or recurrence of the disease. For this reason, surveillance strategies are widely used to screen for early occurrence of cancer in populations at risk. Alpha-foetoprotein is so far the only serological marker available, but its diagnostic accuracy is unsatisfactory because of low sensitivity despite reliable specificity. For this reason, new biomarkers for the diagnosis of hepatocellular carcinoma are in strong demand by clinicians. In this review, we will focus on new biomarkers currently under investigation, but also on still newer, very promising biomarkers that seem to significantly improve diagnosis.

Introduction

Hepatocellular carcinoma (HCC) represents the fifth most frequent malignancy in the world and the third cause of cancer-related death [1]. In the United States, the frequency of HCC has sharply increased in the last few years, whereas the trend for all other malignancies shows a marked decrease [2]. Epidemiological data suggest that in European countries as well as in the United States, the mortality rate from HCC is increasing whereas from liver cirrhosis it is declining [3], [4], [5]. All these reasons explain why HCC is becoming a major health problem worldwide.

Liver cirrhosis (LC) regardless of aetiology, hepatitis B virus and aflatoxin are the most important risk factors for HCC development, and a prediction study based on mathematical models suggests that in the up-coming years the frequency of HCC will increase still further, likely because of the spread of the hepatitis C virus (HCV), strongly correlated to LC [6]. For these reasons, surveillance programs for LC patients were proposed at a Consensus Conference held in Barcelona [7].

Prognosis is still unsatisfactory, even for those patients undergoing liver transplantation; nevertheless, longer survival is closely related to smaller HCC. Therefore, early recognition of HCC is extremely important to the clinical outcome.

Section snippets

Significance of tumour marker

In accordance with the unified medical language system and according to the dictionary of the National Cancer Institute (NCI) a tumour marker is a substance produced by a tumour or by the host, detectable in biological fluids or tissues and useful to differentiate neoplastic from non-neoplastic disease. These markers are commonly used in diagnosis, staging and prognosis of cancer, and can be useful to localise the tumour burden, as well as to monitor therapeutic effectiveness, detect recurrence

The markers used for HCC

The use of a biomarker is of particular relevance for HCC diagnosis because it commonly occurs in patients with LC, considered as the most important risk factor and as pre-malignant disease [8]. The prognosis of advanced HCC is poor, whereas smaller HCC suitable for organ transplantation, surgical resection or radio frequency ablation have shown a better prognosis and longer survival. Therefore, detection of HCC at an early stage heavily affects the clinical outcome of these patients [9], [10],

AFP-L3

The search for new markers for HCC diagnosis has become an important quest by clinicians, as documented by the numbers of papers reported in the literature in the last 15 years (Fig. 1). The chance to screen several molecules in a relatively short time, using highly technological approaches such as genomics, transcriptomics, proteomics, metabolomics and epigenomics has given impetus to research in this field. To avoid the risk of having to handle hundreds of molecules with questionable

Des-gamma carboxy prothrombin (DCP)

DCP is an abnormal prothrombin lacking carboxylation of the 10 glutamic-acid residues in the N-terminus, and is the result of an acquired post-translational defect of the prothrombin precursor in HCC cells, and therefore used as HCC marker [30]. DCP, also known to be induced by Vitamin K absence or antagonist-II (PIVKA-II), does not have any biological coagulative activity.

In 1984, Liebman first reported higher DCP in patients with HCC and also higher levels in patients with recurrence of the

Golgi protein 73 (GP73)

GP73 is a resident Golgi protein, shown to be up-regulated in HCC patients. Marrero reported a sensitivity of 69% and a specificity of 75% in HCC versus cirrhotic patients, using 10 relative units as cut-off, calculated by densitometric scanning of immunoblotting [44]. Although this is a promising study, more investigations are required to confirm these data and clarify the role of this marker in detecting early cancer, considering that these data seem better than those for AFP but not

Glypican-3 (GPC3)

GPC3 is an oncofoetal protein, being a member of the glypican family of heparin sulphate proteoglycans [45], [46]. GPC3 has been reported to be down-regulated in breast cancer, ovarian cancer and lung adenocarcinoma but up-regulated in HCC [47], [48], [49], [50], [51]. GPC3 has been mainly investigated at the tissue levels, although some studies have reported the presence of GPC3 in the sera of about 50% of HCC patients but absence in healthy subjects [52], [53]. In HCC, GPC3 has been shown to

The ‘newer’ generation of biomarkers of HCC

Squamous cell carcinoma antigen (SCCA) is a member of the high molecular weight family of serin protease inhibitors (serpins) [55]. Two different isoforms encoded by two highly homologous genes, SCCA1 and SCCA2, have been identified. Both proteins are physiologically expressed in the suprabasal layer of multi-stratified squamous epithelium [56]. SCCA has been detected in a number of different multi-stratified epithelium-derived malignancies, including the cervix, lung, head and neck [57].

Conflict of interest statement

None declared.

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