**1. Introduction**

Hepatocellular carcinoma (HCC) is a common form of liver cancer associated with high mortality rate [1]. It is estimated that approximately 750,000 new cases of HCC diagnosed per year worldwide which makes HCC as the fifth common cause of cancers affecting human [2]. Mortality rate of approximately 700,000 has been estimated annually due to HCC and it has been considered as the third common cause of death [3].

World Health Organization (WHO) reported that about one million people annually was diagnosed with HCC [4]. The major risk factors for developing HCC are viral infections, alcoholic liver diseases and nonalcoholic steatohepatitis (NASH) [5]. In most of the cases, HCC was diagnosed after the disease progresses, when survival rates are low [6]. Development of HCC is asymptomatic at early stages of the disease when current curative therapies are available [7]. Diagnosis of HCC is based on the combination of radiological, serological and histopathological criteria [8]. Almost 90% of the cases are diagnosed without the help of liver biopsy, as many non-invasive techniques such as serological examination and imaging techniques are used as standard diagnostic test for HCC [9]. Ultrasonography is the most widely used imaging test for screening because of its diagnostic accuracy, non-invasiveness, good acceptance by patients and moderate cost [10].

Because of a large variability in etiological and genetic backgrounds and the long-time development of the disease, HCC lesions are known to exhibit substantial intra-tumor and inter-tumor heterogeneity [11]. For the treatment stratification in HCC, tumor heterogeneity poses a significant challenge [12]. Non-invasive assessment of several tumor characteristics, such as cellularity, perfusion and oxygenation, can be performed using quantitative functional multiparametric magnetic resonance imaging (mpMRI), which can be also used for tumor characterization and for assessing the treatment response [13]. Although pathological and genetic heterogeneity in HCC lesions have been defined, imaging reports on HCC heterogeneity are extremely inadequate, with only one study reporting visual assessment of HCC heterogeneity on contrast-enhanced MRI, with no such study describing quantitative imaging measurements of HCC heterogeneity [14].

Nowadays, magnetic resonance imaging (MRI) analysis has been used to study the characterization of HCC lesions in biopsied or resected samples, and also it provides further information on tumor properties [15]. Without histological confirmation, HCC can be detected using imaging alone in most of the patients, [16], but histopathologic assessment has its own advantage over imaging analysis. Results of the study by Hectors et al. indicated that HCC patients could ultimately benefit from knowledge of about the correlation of imaging parameters with histopathological and genomics properties of HCC lesions [17].

Based on tumor burden, hepatic function and performance status, patient prognosis and treatment decisions are made [18]. Surgical resection and liver transplantation are generally recommended for HCC, but is indicated specifically for patients with early stage and well-preserved liver function [19]. For patients not suitable for curative treatment, transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) may provide better loco-regional tumor control and increase patient survival [20]. It is commonly acknowledged as a palliative treatment option and improves survival in unresectable HCC.

Primary liver cancer or HCC imposes significant challenges to healthcare with huge unmet clinical needs. In males, it is the second leading cause of cancer-related mortality worldwide and 80% of HCC cases are found in the Asia-Pacific regions [21]. Although treatments such as surgical resection, liver transplantation or radiofrequency ablation are potentially curable options for early-stage HCC, recurrences remain the most common issue and limit the overall survival [22]. Survival may be prolonged by loco-regional therapy in intermediate stage HCC and by systemic therapies in advanced HCC [23]. Overall, when compared to other common cancers, clinical outcomes in HCC remain poor due to the lack of effective therapies [24]. It's intrinsically quite challenging to understand the biology of HCC as it is the common end-point of a number of etiologies with different molecular pathways. In addition to increasing the complexity, significant heterogeneity is also existent within the same tumor [25].

**67**

*Translational Perspective in Hepatocellular Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.94769*

cate other treatments [30].

circulating or urinary vesicles [34].

**2. Biomarkers in HCC**

Treatment outcomes for the majority of patients with HCC have remained poor through the years. The overall 5-year survival rate for all patients with HCC has remained steady at 3–5% [26]. This results from two facts. The first major reason is that for most patients, diagnosis is made only when the disease is in advanced stage and inoperable, and the second reason is when the disease has very poor prognosis. Furthermore, cirrhosis of the liver is a major risk factor for HCC development [27]. In most of the cases, the cause of cirrhosis is mainly due to chronic hepatitis B or C virus infection, or heavy alcohol usage [28]. Other known risk factors may include hereditary hemochromatosis, α-1 antitrypsin deficiency, primary biliary cirrhosis, autoimmune hepatitis, smoking and aflatoxin exposure [29]. Regardless of the cause, the accompanying cirrhosis can independently cause death as well as compli-

Because of the challenges faced by current and future populations due to HCC, treatment has been an ever-rising area of interest for research. So far there was no such improved results from cytotoxic therapies have been reported. Researchers' recent efforts have been mainly focused on a variety of proven tactics and techniques [30]. Reducing morbidity and mortality are the major concerns in the modern surgical era, as various studies have recommended that precise evaluation of liver function reserve is indispensable for prognosticating the occurrence of morbidities and mortalities [31]. A number of confounding variables and background liver changes pose a major challenge in clinical proteomics studies that target liver diseases and biomarker discovery. Fat accumulation, inflammation, necrosis, apoptosis, proliferation, fibrosis and viral replication can all occur simultaneously in liver injury [32]. In general, insulin resistance is associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has also been studied, implying hepatitis C as a metabolic disease. As a result, there is a need for novel strategies and careful experimental design [32]. To improve our better understanding of the liver biology, integrative studies such as proteomics and basic cellular biology or other developing fields such as imaging studies and mouse models will play the most prominent role. The translation of basic discoveries into daily clinical practice will accelerate the ability to understand the underlying molecular dysfunction in human disease (such as signaling pathways, protein–protein interaction networks) [32]. A study by Li et al. showed how mouse models of liver disease can be used to provide valuable functional information. Therefore, it helps to improve the current concepts for better screening and prevention [33]. Conde-Vandellis et al., described that biomarker discovery revealed a powerful new path to study proteomic analysis of extracellular,

Various circulating markers and tissue markers have been identified. Because of their low predictive accuracy and/or high cost, few biomarkers are acceptable for clinical utility [35]. Alpha-fetoprotein (AFP) was the first serologic assay for the detection and clinical follow-up of patients with HCC, which has been the standard tumor biomarker for HCC for many years [36]. Analysis of recent studies has indicated that AFP testing lacks adequate sensitivity and specificity for effective surveillance [37]. AFP levels were reported to be normal in up to 40% of patients with HCC, particularly during the early stage of the disease [38]. The combinational use of different biomarkers may enhance the detection sensitivity for the early detection of HCC. The tumor markers are most useful if utilized not only as

confirmatory tests, but also as a part of routine follow-up [39].

#### *Translational Perspective in Hepatocellular Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.94769*

*Translational Research in Cancer*

World Health Organization (WHO) reported that about one million people annually was diagnosed with HCC [4]. The major risk factors for developing HCC are viral infections, alcoholic liver diseases and nonalcoholic steatohepatitis (NASH) [5]. In most of the cases, HCC was diagnosed after the disease progresses, when survival rates are low [6]. Development of HCC is asymptomatic at early stages of the disease when current curative therapies are available [7]. Diagnosis of HCC is based on the combination of radiological, serological and histopathological criteria [8]. Almost 90% of the cases are diagnosed without the help of liver biopsy, as many non-invasive techniques such as serological examination and imaging techniques are used as standard diagnostic test for HCC [9]. Ultrasonography is the most widely used imaging test for screening because of its diagnostic accuracy,

non-invasiveness, good acceptance by patients and moderate cost [10].

quantitative imaging measurements of HCC heterogeneity [14].

logical and genomics properties of HCC lesions [17].

treatment option and improves survival in unresectable HCC.

Because of a large variability in etiological and genetic backgrounds and the long-time development of the disease, HCC lesions are known to exhibit substantial intra-tumor and inter-tumor heterogeneity [11]. For the treatment stratification in HCC, tumor heterogeneity poses a significant challenge [12]. Non-invasive assessment of several tumor characteristics, such as cellularity, perfusion and oxygenation, can be performed using quantitative functional multiparametric magnetic resonance imaging (mpMRI), which can be also used for tumor characterization and for assessing the treatment response [13]. Although pathological and genetic heterogeneity in HCC lesions have been defined, imaging reports on HCC heterogeneity are extremely inadequate, with only one study reporting visual assessment of HCC heterogeneity on contrast-enhanced MRI, with no such study describing

Nowadays, magnetic resonance imaging (MRI) analysis has been used to study the characterization of HCC lesions in biopsied or resected samples, and also it provides further information on tumor properties [15]. Without histological confirmation, HCC can be detected using imaging alone in most of the patients, [16], but histopathologic assessment has its own advantage over imaging analysis. Results of the study by Hectors et al. indicated that HCC patients could ultimately benefit from knowledge of about the correlation of imaging parameters with histopatho-

Based on tumor burden, hepatic function and performance status, patient prognosis and treatment decisions are made [18]. Surgical resection and liver transplantation are generally recommended for HCC, but is indicated specifically for patients with early stage and well-preserved liver function [19]. For patients not suitable for curative treatment, transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) may provide better loco-regional tumor control and increase patient survival [20]. It is commonly acknowledged as a palliative

Primary liver cancer or HCC imposes significant challenges to healthcare with huge unmet clinical needs. In males, it is the second leading cause of cancer-related mortality worldwide and 80% of HCC cases are found in the Asia-Pacific regions [21]. Although treatments such as surgical resection, liver transplantation or radiofrequency ablation are potentially curable options for early-stage HCC, recurrences remain the most common issue and limit the overall survival [22]. Survival may be prolonged by loco-regional therapy in intermediate stage HCC and by systemic therapies in advanced HCC [23]. Overall, when compared to other common cancers, clinical outcomes in HCC remain poor due to the lack of effective therapies [24]. It's intrinsically quite challenging to understand the biology of HCC as it is the common end-point of a number of etiologies with different molecular pathways. In addition to increasing the complexity, significant heterogeneity is also existent

**66**

within the same tumor [25].

Treatment outcomes for the majority of patients with HCC have remained poor through the years. The overall 5-year survival rate for all patients with HCC has remained steady at 3–5% [26]. This results from two facts. The first major reason is that for most patients, diagnosis is made only when the disease is in advanced stage and inoperable, and the second reason is when the disease has very poor prognosis. Furthermore, cirrhosis of the liver is a major risk factor for HCC development [27]. In most of the cases, the cause of cirrhosis is mainly due to chronic hepatitis B or C virus infection, or heavy alcohol usage [28]. Other known risk factors may include hereditary hemochromatosis, α-1 antitrypsin deficiency, primary biliary cirrhosis, autoimmune hepatitis, smoking and aflatoxin exposure [29]. Regardless of the cause, the accompanying cirrhosis can independently cause death as well as complicate other treatments [30].

Because of the challenges faced by current and future populations due to HCC, treatment has been an ever-rising area of interest for research. So far there was no such improved results from cytotoxic therapies have been reported. Researchers' recent efforts have been mainly focused on a variety of proven tactics and techniques [30]. Reducing morbidity and mortality are the major concerns in the modern surgical era, as various studies have recommended that precise evaluation of liver function reserve is indispensable for prognosticating the occurrence of morbidities and mortalities [31]. A number of confounding variables and background liver changes pose a major challenge in clinical proteomics studies that target liver diseases and biomarker discovery. Fat accumulation, inflammation, necrosis, apoptosis, proliferation, fibrosis and viral replication can all occur simultaneously in liver injury [32]. In general, insulin resistance is associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has also been studied, implying hepatitis C as a metabolic disease. As a result, there is a need for novel strategies and careful experimental design [32].

To improve our better understanding of the liver biology, integrative studies such as proteomics and basic cellular biology or other developing fields such as imaging studies and mouse models will play the most prominent role. The translation of basic discoveries into daily clinical practice will accelerate the ability to understand the underlying molecular dysfunction in human disease (such as signaling pathways, protein–protein interaction networks) [32]. A study by Li et al. showed how mouse models of liver disease can be used to provide valuable functional information. Therefore, it helps to improve the current concepts for better screening and prevention [33]. Conde-Vandellis et al., described that biomarker discovery revealed a powerful new path to study proteomic analysis of extracellular, circulating or urinary vesicles [34].
