Targeting tumor vascular endothelial cells for hepatocellular carcinoma treatment

Table 1 Treatments targeting endothelial cells in hepatocellular carcinoma

Category	Treatments	Signaling pathways	Ref.
Tyrosine kinase inhibitor	Apatinib	Suppression of PI3K/AKT/PFKFB3 signaling pathway by selectively inhibiting VEGFR2	[8]
Natural hormone	Melatonin	Restricting the release of ROS and VEGF secretion in human umbilical VECs	[24]
TLR4 inhibitor	TAK-242	Reduction of the endothelial cell population, as well as dendritic cells, Kupffer cells, and neutrophils	[25]
PI3Kγ inhibition	Genetic depletion	Genetic depletion of PI3Kγ in haematopoietic/endothelial cells inhibited neutrophil recruitment and hepatocyte proliferation induced by diethylnitrosamine administration in mice with a high-fat diet	[26]
FABP4 inhibitor	BMS309403	Suppression of tumor growth	[27]
CXCL12 and PD-1 inhibition	A bispecific antibody	Improvement in CD8+ T cell differentiation and suppression of MDSC cell infiltration in the tumor microenvironment	[5]
Anti-PD-1/VEGFR-2 therapy	Anti-PD-1 and anti-VEGFR2 antibodies	Overcoming therapeutic resistance, induction of cytotoxic CD8 T cell infiltration, and reduction of regulatory T cell and monocyte infiltration	[28]
Kruppel-like factor-nitric oxide pathway inhibition	Simvastatin	Inhibiting LSEC capillarization and enhancing natural killer T cells recruitment to suppress HCC	[29]
Circular RNA regulation	Loss of function study	Silencing circular RNA hsa_circ_0003575. Circular RNA can increase oxidized LDL-induced VEC proliferation and angiogenesis	[30]
Long non-coding RNA UBE2CP3	Overexpression	UBE2CP3 overexpression in HCC cells promoted HUVEC proliferation, migration, and tube formation by activating ERK/HIF-1α/p70S6K/VEGFA signaling pathway	[31]
Exosomal delivery of miRNA	MiR-200b-3p	Intratumor delivery of exosomes containing high levels of miR-200b-3p suppressed tumor growth by reducing ERG and VEGF expression and angiogenesis	[32]

PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; VEGFR2: Vascular endothelial growth factor receptor 2; ROS: Reactive oxygen species; VEGF: Vascular endothelial growth factor; VEC: Vascular endothelial cell; TLR-4: Toll-like receptor 4; FABP4: Fatty liver binding protein 4; CXCL12: C-X-C motif chemokine ligand 12; PD-1: Programmed cell death protein 1; MDSC: Myeloid-derived suppressor cell; LSEC: Liver sinusoidal endothelial cell; LDL: Low density lipoprotein; UBE2CP3: Ubiquitin conjugating enzyme E2C pseudogene 3; HUVECs: Human umbilical vein endothelial cells; ERK: Extracellular signal-regulated kinase; HIF: Hypoxia inducible factor; P70S6K: Ribosomal protein S6 kinase beta-1; VEGFA: Vascular endothelial growth factor A.