Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies

Abstract

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Angiogenesis, the process of formation of new blood vessels, is required for cancer cells to obtain nutrients and oxygen. HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth, progression, invasion, and metastasis. Current anti-angiogenic therapies target mainly tyrosine kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), and are considered effective strategies for HCC, particularly advanced HCC. However, because the survival benefits conferred by these anti-angiogenic therapies are modest, new anti-angiogenic targets must be identified. Several recent studies have determined the underlying molecular mechanisms, including pro-angiogenic factors secreted by HCC cells, the tumor microenvironment, and cancer stem cells. In this review, we summarize the roles of pro-angiogenic factors; the involvement of endothelial cells, hepatic stellate cells, tumor-associated macrophages, and tumor-associated neutrophils present in the tumor microenvironment; and the regulatory influence of cancer stem cells on angiogenesis in HCC. Furthermore, we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC. A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.

Keywords: Angiogenesis; anti-angiogenic therapy; hepatocellular carcinoma; pro-angiogenic factors; tumor microenvironment.

Figure 1

Mechanisms of pro-angiogenic factors inducing angiogenesis and new potential targets inhibiting angiogenesis in HCC. Pro-angiogenic factors secreted by HCC cells, including VEGFA, Ang2, FGF2, PDGFA, CXCL12, and TGF-β, bind the receptors expressed on ECs and promote angiogenesis in HCC. Hypoxia promotes expression of VEGFA, FGF2, and PDGFA in HCC cells. Leptin also promotes VEGFA expression by binding Ob-R in HCC cells. VEGFA binds VEGFR2 and subsequently activates the PI3K/AKT and RAF/MAPK pathways, thereby promoting angiogenesis. By interacting with FGFR1, FGF2 promotes angiogenesis in HCC by activating the RAF/MAPK pathway. PDGFA activates MEK/ERK signaling via PDGFR, thus promoting angiogenesis. TGF-β binds CD105 and activates the ALK/SMAD1/5 pathway, which promotes angiogenesis. COX2 and VEGFA induced Ang2 promotes angiogenesis by binding the Tie2 receptor. SOX4 induced CXCL12 promotes angiogenesis by binding the CXCR4 receptor. Nvp-bep800 inhibits HSP90β in ECs and subsequently attenuates angiogenesis in HCC. AMD3100 inhibits CXCR4 on ECs, thus attenuating angiogenesis in HCC. TRC105 inhibits CD105 on ECs and consequently attenuates angiogenesis in HCC.

Figure 2

Schematic representation of TME associated cells mediating angiogenesis in HCC. The HSCs undergo a phenotypic transformation, from quiescent type to a-HSCs or to transdifferentiated CAFs, which secrete pro-angiogenic factors or cytokines that promote angiogenesis in HCC. The M2-like TAMs and TANs also secrete pro-angiogenic factors or cytokines that promote angiogenesis in HCC. PDGF-BB and SHh secreted by HCC cells activates HSC, and a-HSCs release VEGFA, IL8, CNN, Angs, and PDGFB, which in turn promote angiogenesis. Exosomal miR-21 converts HSCs to CAFs, which in turn promote angiogenesis by secreting VEGF, MMP2, MMP9 and TGF-β. LncRNA cox-2, miR-140, and CSF-1 facilitate the polarization of macrophages toward the M2 subtype, which secretes IL-10, TGF-β, and PGE2 and consequently promotes angiogenesis in HCC. TGF-β and IL-17 stimulate TANs to secrete MMP9, BV8, and S100A8/9, which promote angiogenesis in HCC.

Figure 3

Mechanisms of CSCs in HCC angiogenesis. SOX2 and c-MYC regulate lncRNA n339260, thus promoting VM through the induction of a CSC-like phenotype in HCC. FZD2 also promotes VM through the induction of the CSC-like phenotype through the YAP/TAZ pathway. Meanwhile, CSCs promote angiogenesis by secreting IL8 and CXCL1 through the RAF/ERK pathway, or secreting VEGF through the Src/FAK pathway. CSCs also secrete lncRNA H19 and DDK1, thus promoting angiogenesis in HCC.