Targeting tumor vascular endothelial cells for hepatocellular carcinoma treatment

Figure 1 Vascular endothelial cells play multiple roles in the hepatocellular carcinoma microenvironment. All cartoons in this figure were prepared using Biorender (Supplementary material). A: Inflammation. The ligand-receptor interactions, such as vascular endothelial growth factor (VEGF) A-FLT1 [VEGF receptor 1 (VEGFR1)] or VEGFR2/KDR, stromal cell-derived factor 1 (or C-X-C motif chemokine ligand 12)-C-X-C chemokine receptor type 4 (CXCR4), and interleukin-1A/interleukin-1R1, mediate vascular endothelial cell communication with other cells (e.g., macrophages) to regulate inflammation and tumor cell growth; B: Fibrosis. Platelet-derived growth factor produced by endothelial cells can stimulate hepatic stellate cell activation by binding its receptor platelet-derived growth factor receptor to promote liver fibrosis; C: Angiogenesis. Tumor vascular endothelial cells can interact with monocytes/macrophages, and T cells/natural killer cells through MIF-CD74 plus CXCR4/CD44 and VEGFA-VEGFR1/2 ligand-receptor interactions to induce the recruitment of immunosuppressive cells and promote angiogenesis; D: Hepatocellular carcinoma (HCC) progression. For example, overexpression of ephrin receptor A1 protein in HCC tumor cells can increase C-X-C motif chemokine ligand 12 expression to recruit CXCR4-expressing endothelial progenitor cells into the tumor microenvironment to promote vascularization and HCC progression. VEGFA: Vascular endothelial growth factor A; CXCL12: C-X-C motif chemokine ligand 12; IL: Interleukin; ICAM-1: Intercellular adhesion molecule 1; HCC: Hepatocellular carcinoma; LSEC: Liver sinusoidal endothelial cell; LOX: Lysyl oxidase; FN1: Fibronectin 1; PDGF: Platelet-derived growth factor; PDGFR: Platelet-derived growth factor receptor; HSC: Hepatic stellate cell; CXCR4: C-X-C chemokine receptor type 4; VEGFR: Vascular endothelial growth factor receptor; VACAM-1: Vascular adhesion molecule 1; VEGF: Vascular endothelial growth factor; NK: Natural killer; VEC: Vascular endothelial cell; EphA1: Ephrin receptor A1; SDF-1: Stromal cell-derived factor 1.