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.

Characteristic of molecular subtypes based on PANoptosis-related genes and experimental verification of hepatocellular carcinoma

“…The formation of new blood vessels in the TME can provide the tumor with nutrients and oxygen needed for growth. The immune system’s response to the tumor can impact the prognosis [ 7 ]. A strong immune response can slow tumor growth, while a weak immune response can allow the tumor to grow unchecked [ 8 ].…”

Tumor biomarkers for diagnosis, prognosis and targeted therapy

“… 1089 Common clinical adverse effects of sorafenib include diarrhea, fatigue, skin reactions on the hands and feet, rash or desquamation, and anorexia. 416 Lenvatinib, an oral TKI that targets VEGFR, FGFR, PDGFR, KIT, and RET, exerts antiproliferative and immunomodulatory activity in preclinical cancer models, and has been approved as a first-line treatment for HCC. Compared with sorafenib, levatinib has improved OS and PFS in patients with HCC.…”

“… 1090 The most common adverse effects of lenvatinib treatment include hypertension, diarrhea, loss of appetite, weight loss, and fatigue. 416 Sunitinib, an oral TKI targeting VEGFR1-3, PDGFR, FLT-3, and c-Kit, 401 , 1085 is approved by the FDA for the treatment of refractory GIST and metastatic RCC. 401 There are clinical studies using sunitinib for the treatment of advanced or metastatic breast cancer and NSCLC.…”

Emerging role of exosome-derived non-coding RNAs in tumor-associated angiogenesis of tumor microenvironment

“…The overexpression of exosome-derived miR-16 and miR-100 from mesenchymal stem cells downregulates VEGF expression in breast cancer cells, thus inhibiting angiogenesis and tumor growth in vivo and in vitro (Soheilifar et al, 2022). In hepatoma cells, cancer stem cells upregulate VEGF by delivering overexpressed lncRNAH19 to ECs to promote angiogenesis and tumor growth (Yao et al, 2023). TAM-derived exosomes are enriched with miR-501-3p, which enhances the metastatic capacity of pancreatic ductal adenocarcinoma (PDAC) cells (Yin et al, 2019;Cocks et al, 2022).…”