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The Role of Signaling Pathways in the Development and Treatment of Hepatocellular Carcinoma

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The Role of Signaling Pathways in the Development and Treatment of Hepatocellular Carcinoma Oncogene (2010) 29, 4989–5005 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW The role of signaling pathways in the development and treatment of hepatocellular carcinoma S Whittaker1,2, R Marais3 and AX Zhu4 1Dana-Farber Cancer Institute, Boston, MA, USA; 2The Broad Institute, Cambridge, MA, USA; 3Institute of Cancer Research, London, UK and 4Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA Hepatocellular carcinoma (HCC) is a highly prevalent, malignancy in adults (Pons-Renedo and Llovet, 2003). treatment-resistant malignancy with a multifaceted mole- For the vast majority of patients, HCC is a late cular pathogenesis. Current evidence indicates that during complication of chronic liver disease, and as such, is hepatocarcinogenesis, two main pathogenic mechanisms often associated with cirrhosis. The main risk factors for prevail: (1) cirrhosis associated with hepatic regeneration the development of HCC include infection with hepatitis after tissue damage caused by hepatitis infection, toxins B virus (HBV) or hepatitis C virus (HCV). Hepatitis (for example, alcohol or aflatoxin) or metabolic influ- infection is believed to be the main etiologic factor in ences, and (2) mutations occurring in single or multiple 480% of cases (Anzola, 2004). Other risk factors oncogenes or tumor suppressor genes. Both mechanisms include excessive alcohol consumption, nonalcoholic have been linked with alterations in several important steatohepatitis, autoimmune hepatitis, primary biliary cellular signaling pathways. These pathways are of cirrhosis, exposure to environmental carcinogens (parti- interest from a therapeutic perspective, because targeting cularly aflatoxin B) and the presence of various genetic them may help to reverse, delay or prevent tumorigenesis. metabolic diseases (for example, hereditary hemo- In this review, we explore some of the major pathways chromatosis, tyrosinemia and a1-antitrypsin deficiency; implicated in HCC. These include the RAF/MEK/ERK Llovet et al., 1999; Roberts and Gores, 2005; Thomas pathway, phosphatidylinositol-3 kinase (PI3K)/AKT/ and Abbruzzese, 2005). mammalian target of rapamycin (mTOR) pathway, One of the main reasons for the high mortality rate in WNT/b-catenin pathway, insulin-like growth factor patients with HCC is the lack of effective treatment pathway, hepatocyte growth factor/c-MET pathway and options, especially for those with advanced disease. growth factor-regulated angiogenic signaling. We focus on Although surgery and percutaneous ablation can the role of these pathways in hepatocarcinogenesis, how achieve long-term control in some patients with early they are altered, and the consequences of these abnor- HCC, recurrence rates are high (approximately 50% malities. In addition, we also review the latest preclinical at 3 years; Mulcahy, 2005). Moreover, because of the and clinical data on the rationally designed targeted asymptomatic nature of early HCC, lack of awareness agents that are now being directed against these pathways, and poorly defined screening strategies, most patients with early evidence of success. (approximately 80%) present with advanced or unre- Oncogene (2010) 29, 4989–5005; doi:10.1038/onc.2010.236; sectable disease (Thomas and Abbruzzese, 2005). These published online 19 July 2010 patients generally have a very poor prognosis and treatment options are mainly palliative. Even with Keywords: epidermal growth factor receptor; hepato- treatment (such as transarterial chemoembolization, cellular carcinoma; multikinase inhibitor; signaling; intra-arterial or systemic chemotherapy, radiotherapy, sorafenib; vascular endothelial growth factor immunotherapy or hormonal therapy), the 5-year relative survival rate for patients with HCC is only 7%, and very few patients with symptomatic disease Introduction survive for 41 year (Bosch et al., 2004). The paucity of effective and well-tolerated treatments for advanced Liver cancer is the sixth most common malignancy and HCC (Simonetti et al., 1997; Zhu, 2006) highlights the the third most common cause of cancer-related morta- need for new therapeutic approaches. lity worldwide (Parkin et al., 2005). Hepatocellular In recent years, improved knowledge of oncogenic carcinoma (HCC) is the most common primary liver processes and the signaling pathways that regulate tumor cell proliferation, differentiation, angiogenesis, invasion and metastasis has led to the identification of Correspondence: Dr AX Zhu, Massachusetts General Hospital Cancer several possible therapeutic targets that have driven the Center, Harvard Medical School, Lawrence House/POB 232, 55 Fruit development of molecularly targeted therapies. These Street, Boston, MA 02114, USA. E-mail: [email protected] drugs, which act directly on components of the signaling Received 4 March 2010; accepted 13 May 2010; published online 19 July pathways regulating tumorigenesis, have showed clinical 2010 benefit in patients with various tumor types, including HCC signaling review S Whittaker et al 4990 colorectal, renal, breast and lung cancers, and more larly, tumor growth, vascular invasion (the hallmark of recently, HCC. Because many of the pathways are invasive disease) and metastasis are also critically implicated in the pathogenesis of various tumor types, dependent on efficient angiogenesis (Semela and Du- targeted agents seem to be effective in more than one four, 2004). In HCC, angiogenesis relies on autocrine malignancy. Here we review several major molecular and paracrine interactions between tumor cells, vascular signaling pathways implicated in the pathogenesis of endothelial cells and pericytes (Figure 3) (Folkman, HCC. In addition, we explore the rationale for targeting 2003; Roberts and Gores, 2006). During the angiogenic molecular components of these signaling pathways, process, the existing microvasculature is destabilized, describe the preclinical activity of targeted therapies leading to vascular hyperpermeability, remodeling of the currently in development and approved for HCC, and cellular matrix and activation of endothelial cells briefly review the evidence for their clinical activity in (Papetti and Herman, 2002). Once activated, endothelial patients with HCC. cells proliferate, migrate and undergo cord formation to form new microvessels (Papetti and Herman, 2002). Finally, pericytes are activated and recruited to stabilize Search strategy and selection criteria the new blood vessels. Normal angiogenesis is maintained by the balance Data on the molecular drivers of HCC were identified between proangiogenic and antiangiogenic factors (Seme- for this review by searches of MEDLINE, EMBASE, la and Dufour, 2004). The angiogenic balance is disturbed BIOSIS, ISI and PubMed. Only papers published in in HCC as tumor cells, endothelial cells and pericytes English from 1987 to 2010 were assessed. Recent (2006– secrete a net excess of angiogenic factors, which support 2010) abstracts and reports from meetings were also the recruitment and activation of endothelial cells included if relevant. In addition, the clinicaltrials.gov and pericytes. A number of angiogenic growth factors, website was used to identify studies of agents of including VEGF-A, angiopoietin-2 and PDGF, have been potential interest in HCC. shown to be upregulated in HCC tumors at the level of gene expression and at the plasma protein level in patients with HCC compared with cirrhotic patients (Mas et al., Signaling transduction pathways implicated in HCC 2007). The principal angiogenic factors involved are VEGFs, PDGFs, placental growth factors, transforming HCC has a very complex molecular pathogenesis in growth factor (TGF)-a and -b, basic fibroblast growth which two mechanisms predominate: (1) cirrhosis factor, EGF, HGF, angiopoietins and interleukin-4 and -8 associated with hepatic regeneration after tissue damage (Folkman, 2003; Semela and Dufour, 2004). These growth caused by hepatitis infection, toxin/environmental fac- factors and cytokines induce angiogenic signaling through tors (for example, alcohol or aflatoxin B) or metabolic a variety of mechanisms, including activation of the influences (for example, insulin resistance, obesity, type RAF/MEK/ERK, PI3K/AKT/mTOR and Janus kinase II diabetes or dyslipidemia in nonalcoholic steatohepa- (JAK)/signal transducer and activator of transcription titis-induced HCC; Bugianesi, 2005); and (2) mutations pathways (Roberts and Gores, 2005). occurring in one or more oncogenes or tumor suppres- sor genes (Figure 1) (Thorgeirsson and Grisham, 2002; Wang et al., 2002; Feitelson et al., 2004; Marotta et al., VEGF receptor signaling 2004; Villanueva et al., 2007, 2008). Both of these mechanisms have been associated with abnormalities in One of the most intensely studied growth factors several critical cell signaling pathways that perpetuate involved in angiogenesis is VEGF. Studies of human the carcinogenic process. These signaling cascades are of tumor xenografts in immunodeficient mice showed that interest from a therapeutic perspective, because target- neutralization of VEGF inhibited tumor growth and ing them may help to reverse, delay or prevent hepato- decreased blood vessel density in a variety of tumor carcinogenesis. In this respect, growth factor-mediated types (Kim et al., 1993). Overexpression of VEGF angiogenic signaling (vascular endothelial growth factor may be induced by the hypoxic tumor environment (VEGF), platelet-derived growth factor (PDGF), (mediated by hypoxia-inducible
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