Several studies tested neutralizing antibodies against mature VEGF proteins, blockade of VEGF receptors by VEGF receptor antibodies, soluble VEGF receptor mutants or fusion-proteins, and intra-cellular interference with VEGF mRNA or kinase signaling pathways in the target cell. Inhibiting the process of angiogenesis by knocking out the activity of VEGF has a significant impact Ivacaftor cell line on tumor growth and patient survival. However, it does not seem to be enough for a complete cure. So it is still necessary to explore as many regulatory steps as possible in the complex sequence of tumor-induced angiogenesis. Besides the VEGF, FGF and its family of receptors (FGFR) are potent

inducers of angiogenesis in HCC.4,5 Elevated serum FGF levels are an important prognostic factor in HCC,6 and the aberrant activation of FGFR has been shown to drive hepatocarcinogenesis.7 FGF might also modulate the resistance to VEGF/VEGFR inhibition. For example, FGF2 has been shown to synergistically augment the VEGF-mediated HCC development and angiogenesis8 and might play a central role in the “escape mechanisms” implicated in VEGF/VEGFR targeting. Clinical and translational studies suggest that FGF blockade might circumvent resistance to

the VEGFR modulating agents.9 In a study of patients undergoing surgery for HCC, the high serum levels of FGF2 was shown to be a predictor for invasiveness and recurrence.10 Although the VEGF inhibitors can reduce the growth of the primary tumors, there are data HIF-1 activation showing that they might also Axenfeld syndrome promote the invasiveness and metastasis of the tumor.11 Accordingly, novel anti-angiogenic therapies targeting FGF to synergize with VEGF-mediated anti-angiogenesis might provide a mechanism to overcome resistance to VEGF-targeted agents in HCC. So we should use the knowledge to inhibit the process of angiogenesis at a more sensitive point of angiogenesis, or at several

points simultaneously. To achieve this goal, the newly developed in vitro models of tumor growth and of blood vessel formation could be helpful. Actually, several agents that target the VEGF pathway have been tested in patients with advanced HCC, such as the oral multikinase inhibitors, sorafenib and sunitinib, whose antitumor effects are partly as a result of the inhibition of VEGF receptors. Although the SHARP trial showed only a 2.8-month improvement in median overall survival rate (P = 0.0006), along with very limited increased time to disease progression and disease control rate, and a 2.3% response rate, sorafenib became the first targeted agent approved to use in advanced HCC by the USA Food and Drug Administration.12 The monoclonal antibody against VEGF, bevacizumab, either used alone or in combination with erlotinib, has shown improved survival in advanced HCC patients. In this issue of the Journal, Jie et al.