New Insight into Therapies Targeting Angiogenesis in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a malignancy characterized by neoangiogenesis that is determined by an augmented production of proangiogenesis factors by tumor and adjacent cells. This unbalanced angiogenesis process is a key feature of HCC carcinogenesis and progression. Proangiogenic factors also have a relevant role in the generation and maintenance of an immunosuppressive tumor microenvironment. Several therapeutic options for HCC treatment are based on the inhibition of angiogenesis, both in the early/intermediate stages of the disease and in the late stages of the disease. Conventional treatment options employing antiangiogenic approaches provide for the starving of tumors of their blood supply to avoid the refueling of oxygen and nutrients. An emerging alternative point of view is the normalization of vasculature leading to enhance tumor perfusion and oxygenation, potentially capable, when proposed in combination with other treatments, to improve delivery and efficacy of other therapies, including immunotherapy with checkpoint inhibitors. The introduction of novel biomarkers can be useful for the definition of the most appropriate dose and scheduling for these combination treatment approaches. The present review provides a wide description of the pharmaceutical compounds with an antiangiogenic effect proposed for HCC treatment and investigated in clinical trials, including antibodies and small-molecule kinase inhibitors.

Keywords: HCC; angiogenesis; immunotherapy; small-molecule kinase inhibitors.

Figure 1

Antiangiogenic therapeutic strategies considered in the present review. TACE: transarterial chemoembolization.

Figure 2

Molecular targets of antiangiogenic therapies. (a) molecur targets in endothelial cells, (b) molecular targets in tumor cells.

Figure 3

Immunosuppressive role of angiogenic factors. (a) Schematic representation of tumor microenvironment actors in a non-treated situation. (b) Schematic representation of tumor microenvironment actors in a treated situation. Abbreviations: Ang-2 = angiopoietin-2; DC = dendritic cell; FasL = Fas ligand; ICAM-1 = intercellular adhesion molecule-1; IL-10 = interleukin-10; LFA-1 = lymphocyte function-associated antigen 1; MDSC = myeloid-derived stem cells; TAM = tumor associated macrophages; TEM = TIE-2 expressing monocyte; TIE-2 = angiopoietin receptor; Tregs = regulatory T lymphocytes; VCAM-1 = vascular cell adhesion molecule-1; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; VLA-1 = very late antigen-1.