Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, showing a rapid progressive clinical course, poor response to pharmacological treatment and a severe prognosis (Colombo, 2003; Sherlock & Dooley, 2002). HCC generally develops from chronic liver injury, which leads to inflammation, hepatocyte regeneration, liver matrix remodeling, fibrosis, and finally, cirrhosis. The main risk factors for HCC are hepatitis B (HBV) or C virus (HCV) infection, alcohol-induced liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis and exposure to environmental carcinogens (particularly aflatoxin), and genetic metabolic diseases. (Chuang et al., 2009; Di Bisceglie, 1995; Kato et al, 1994; Malaguarnera et al., 2006; Malaguarnera et al., 2009; Seitz & Becker, 2007; Takano et al., 1995). Obesity has also been identified as an independent risk factor for developing HCC in patients with alcoholic or cryptogenic cirrhosis (Nair et al, 2002). Actually, HCV-related cirrhosis is considered the major risk factor since many HCV chronically infected patients remain asymptomatic for a long period, with liver cirrhosis developing after approximately 30 years (Yano et al., 1996; Poynard et al., 1997). The lack of predictive markers that makes unforeseeable the insurgence of liver cirrhosis in chronic HCV patients may also contribute to HCC late diagnosis, progression and poor prognosis. Currently, alpha-fetoprotein (AFP) is the most common marker for early malignancy used in clinical practice, in combination with hepatic echography, to detect HCC in patients suffering from cirrhosis. Nevertheless, most episodes of AFP elevation were transient and closely correlated with the presence of bridging hepatic necrosis, without subsequent development of HCC (Liaw et al., 1986). Since an early diagnosis of HCC is extremely important in improving the survival of patients, the identification of new and more reliable biological markers of HCC insurgence, recurrence and metastasis is essential for the proper management of this malignancy. Once hepatic cancer develops, one of the main reasons for the high mortality rate in patients with HCC is the lack of effective treatment options, especially for those with advanced disease. Although surgery and percutaneous ablation can achieve long-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 survival rate of only 7% (Bosch et al., 2004). 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 individual tumor. 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.
New Molecular Biomarkers Candidates for the Development of Multiparametric Platforms for Hepatocellular carcinoma Diagnosis, Prognosis and Personalised Therapy
Annalucia Serafino;Pasquale Pierimarchi
2012
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, showing a rapid progressive clinical course, poor response to pharmacological treatment and a severe prognosis (Colombo, 2003; Sherlock & Dooley, 2002). HCC generally develops from chronic liver injury, which leads to inflammation, hepatocyte regeneration, liver matrix remodeling, fibrosis, and finally, cirrhosis. The main risk factors for HCC are hepatitis B (HBV) or C virus (HCV) infection, alcohol-induced liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis and exposure to environmental carcinogens (particularly aflatoxin), and genetic metabolic diseases. (Chuang et al., 2009; Di Bisceglie, 1995; Kato et al, 1994; Malaguarnera et al., 2006; Malaguarnera et al., 2009; Seitz & Becker, 2007; Takano et al., 1995). Obesity has also been identified as an independent risk factor for developing HCC in patients with alcoholic or cryptogenic cirrhosis (Nair et al, 2002). Actually, HCV-related cirrhosis is considered the major risk factor since many HCV chronically infected patients remain asymptomatic for a long period, with liver cirrhosis developing after approximately 30 years (Yano et al., 1996; Poynard et al., 1997). The lack of predictive markers that makes unforeseeable the insurgence of liver cirrhosis in chronic HCV patients may also contribute to HCC late diagnosis, progression and poor prognosis. Currently, alpha-fetoprotein (AFP) is the most common marker for early malignancy used in clinical practice, in combination with hepatic echography, to detect HCC in patients suffering from cirrhosis. Nevertheless, most episodes of AFP elevation were transient and closely correlated with the presence of bridging hepatic necrosis, without subsequent development of HCC (Liaw et al., 1986). Since an early diagnosis of HCC is extremely important in improving the survival of patients, the identification of new and more reliable biological markers of HCC insurgence, recurrence and metastasis is essential for the proper management of this malignancy. Once hepatic cancer develops, one of the main reasons for the high mortality rate in patients with HCC is the lack of effective treatment options, especially for those with advanced disease. Although surgery and percutaneous ablation can achieve long-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 survival rate of only 7% (Bosch et al., 2004). 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 individual tumor. 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
