Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization, which plays an important role in the growth and progression of HCC. Angiogenesis provides a target for novel prognostic and therapeutic approaches to HCC. Assessment of microvessel density using immunohistochemical staining for specific endothelial cell markers such as CD34 has been shown to provide prognostic information independent of conventional pathological parameters in HCC patients. Recent studies have unveiled the important angiogenic factors involved in the regulation of angiogenesis in HCC, although the exact molecular pathways are far from clear. Current data suggest that vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis of HCC. Tumor expression of VEGF has been shown to correlate with tumor invasiveness and prognosis in patients with HCC. VEGF is an important molecular target for antiangiogenic therapy. Studies in animal models have demonstrated the efficacy of antiangiogenic agents such as anti-VEGF antibody and antagonists of VEGF receptors in suppressing hepatocarcinogenesis and growth of HCC. Antiangiogenic therapy has already entered clinical trials in HCC patients and holds the promise of providing an effective novel treatment for HCC, which is of great clinical significance because there is no existing effective systemic therapy for HCC.

Introduction

Hepatocellular carcinoma is one of the five most common cancers worldwide, with a particularly high prevalence in Asian countries due to endemic hepatitis B virus infection [1]. The incidence of HCC is also rising in Western countries as a result of increasing hepatitis C virus infection [2]. More than 80% of patients with HCC have associated cirrhosis and impaired liver function, making treatment of HCC more difficult than many other cancers. Surgical resection is the mainstay of curative treatment for HCC, but prognosis after resection remains unsatisfactory due to a high incidence of postoperative recurrence [3]. Liver transplantation is another potentially curative treatment for early HCC associated with advanced cirrhosis, but its application is limited by the shortage of grafts [4]. For unresectable HCC, various locoregional therapies may be used to palliate symptoms and prolong survival if the tumors remain confined to the liver [5]. Conventional cytotoxic chemotherapy has not been shown to be effective for HCC, and there is no proven effective systemic therapy for HCC patients with metastatic disease [6]. Hence, the search for a novel systemic therapy for HCC is of paramount importance.

Understanding the molecular pathways of HCC is crucial to the development of novel therapies for this highly aggressive cancer [7]. Molecular mechanism regulating angiogenesis is one of the potential targets for novel therapies for HCC. HCC is one of the most vascular solid cancers, associated with a high propensity for vascular invasion. In fact, its active neovascularization can be visualized in angiography and is used as a diagnostic criterion for HCC. Tumor angiogenesis plays a critical role in the development and progression of HCC. The emerging success of antiangiogenic therapy for other cancers such as colorectal cancer [8], [9] and lung cancer [10] has brought hope of the potential use of antiangiogenic therapy for HCC, which is a particularly attractive approach because of the vascularity of HCC and the current lack of effective systemic therapies for HCC. In this article, we review the recent progress of research on molecular mechanisms of angiogenesis and the potential clinical implications in HCC.