Figure 1.

Angiopoietin-2-mediated vascular sprouting in hepatocellular carcinoma. Vascular remodeling is crucial for the growth and progression of hepatocellular carcinoma (HCC) [12,13]. The formation of new blood vessels is induced by the angiogenic switch, which implies an intratumoral balance shift in favor of proangiogenic factors, including vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 [15,16,17,18]. Overexpression of Ang-2 may be mediated by hypoxia [28], VEGF overexpression [29], cyclooxygenase (COX)-2 overexpression [30] and AT-rich interactive domain-containing protein 1A (Arid1a) deficiency [31], among others, and alters the quantitative balance between Ang-1 and Ang-2 expression in favor of Ang-2 [21]. Subsequent interaction with its receptor, tyrosine kinase with immunoglobulin (Ig) and epidermal growth factor (EGF) homology domains 2 (Tie2), which are predominantly expressed on the surface of endothelial cells, result in vessel destabilization and, thereby, facilitates other proangiogenic factors, including VEGF, to induce vascular sprouting [32,33]. Ang-2 is thus dependent on VEGF/VEGF receptor (VEGFR) signaling to exert its effect on HCC angiogenesis and progression [27]. Despite the complexity of Ang-2-mediated HCC neovascularization, Ang-2 could potentially serve as a circulating or tissue biomarker for HCC, and therapeutic opportunities lie in direct or indirect targeting of this Ang-2/Tie2 signaling pathway. This figure was created with BioRender.com.