**2. Biological markers useful for early diagnosis of HCC insurgence, recurrence and metastasis**

Currently, the diagnosis of HCC is mainly based on the atypical histopathology of bioptic liver tissues, combined with the laboratory screening including the index of hepatic damage (alanine aminotransferase and aspartate aminotransferase), the index of hepatic synthesis (albumin, prothrombin time, bilirubin), the index of cholestasis (alkaline phosphatase and gamma-glutamyl transpeptidase), and finally, tumor markers and instrumental analyses, including hepatic ultrasonography, computed tomography, nuclear magnetic resonance. Some of the tumor markers for HCC diagnosis, such as alpha-fetoprotein (AFP), *lens culinaris* agglutinin-reactive AFP (AFP-L3) and des-γ-carboxyprothrombin (DCP) have now been incorporated into HCC staging classification (Marrero et al., 2010) and are routinely taken into account for the screening for early malignancy (**Table 1**). Other biomarkers, including some growth factors, such as Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor β1 (TGF-β1), Hepatocyte Growth Factor EGF), Epidermal

term control in some patients with early HCC, recurrence rates are high, approximately 50% at 3 years (Mulcahy, 2005). Furthermore, due to the asymptomatic nature of early HCC, lack of awareness and poorly defined screening strategies, approximately 80% of patients present with advanced or unresectable disease (Thomas & Abbruzzese, 2005). These patients generally have a very poor prognosis and treatments, such as transarterial chemoembolization, intra-arterial or systemic chemotherapy, radiotherapy, immunotherapy or hormonal therapy, are mainly used as palliative, with a 5-year relative

The lack of effective and well-tolerated treatments for advanced HCC highlights the need for innovative approaches for diagnosis, prognosis and therapy for hepatic cancer. In this context, multiparametric platforms allowing simultaneous detection of multiple serological and immunohistochemical markers for HCC insurgence, recurrence and metastasis would represent a high-performance technological tools useful not only for diagnosis and prognosis, but also for improving the clinical management of HCC patients, allowing us, in the near future, to design therapies adapted to the aggressiveness of each

Starting from this background, in this chapter will be collected some of the data existing in literature on the main serological and immunohistochemical biomarkers for HCC diagnosis, prognosis and target therapy, also focusing on new molecules which might be attractive candidates for improvement of the diagnostic/therapeutic approaches. In particular will be covered the following topics : 1) Some new candidates recently proposed as potential biological markers of HCC insurgence, recurrence and metastasis, that could be useful for early diagnosis of this malignancy and improve patient's prognosis; 2) Some signaling pathways which deregulation or constitutive activation have been demonstrated to have a role in HCC insurgence and progression and that could be of interest for therapeutic perspectives, since targeting them may contribute to prevent tumorigenesis or achieve tumor reversion; 3) Molecules over-expressed in late stages of cancer or in the metastatic

diseases that should be considered a good targets for therapy and drug delivery.

**2. Biological markers useful for early diagnosis of HCC insurgence,** 

Currently, the diagnosis of HCC is mainly based on the atypical histopathology of bioptic liver tissues, combined with the laboratory screening including the index of hepatic damage (alanine aminotransferase and aspartate aminotransferase), the index of hepatic synthesis (albumin, prothrombin time, bilirubin), the index of cholestasis (alkaline phosphatase and gamma-glutamyl transpeptidase), and finally, tumor markers and instrumental analyses, including hepatic ultrasonography, computed tomography, nuclear magnetic resonance. Some of the tumor markers for HCC diagnosis, such as alpha-fetoprotein (AFP), *lens culinaris* agglutinin-reactive AFP (AFP-L3) and des-γ-carboxyprothrombin (DCP) have now been incorporated into HCC staging classification (Marrero et al., 2010) and are routinely taken into account for the screening for early malignancy (**Table 1**). Other biomarkers, including some growth factors, such as Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor β1 (TGF-β1), Hepatocyte Growth Factor EGF), Epidermal

survival rate of only 7% (Bosch et al., 2004).

individual tumor.

**recurrence and metastasis** 

Growth Factor receptor (EGFR), and numerous other molecules (**Table 1**), are used as diagnostic/prognostic aid for HCC and for staging (Malaguarnera et al., 2010; Mann et al., 2007; Qin & Tang, 2004). Nevertheless, each existing marker alone is poorly specific to predict the disease and most markers are not related to each other. Currently the absolute positive and negative serological and/or immunohistochemical markers for HCC are still lacking, and even those selected for high sensitivity and specificity do not exhibit an universal diagnostic/prognostic value. Therefore, in the last years, a great number of studies has been dedicated to the discovery and validation of more specific biomarkers for HCC, driven by the idea that the simultaneous screening for multiple markers should greatly reduce errors from false-negative results, which significantly contribute to an incorrect diagnosis.
