New Insight into Therapies Targeting Angiogenesis in Hepatocellular Carcinoma

Mossenta, Monica; Busato, Davide; Baboci, Lorena; Cintio, Federica Di; Toffoli, Giuseppe; Bo, Michele Dal

doi:10.3390/cancers11081086

Cited by 43 publications

(33 citation statements)

References 113 publications

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“…HCC is a highly angiogenic cancer (71,72), and therefore antiangiogenic therapy is an effective strategy in the treatment of HCC. LOX-L2 inhibitors could be potent combination partners for the antiangiogenic drugs approved for the treatment of HCC such as Cabometyx, Cyramza, Lenvatinib Mesylate, Ramucirumab and Sorafenib Tosylate (73,74). The present study revealed a potential role of LOXL2 in HCC, which may provide new insights into the treatment of HCC.…”

Section: Discussionmentioning

confidence: 51%

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

Fan

Zheng

et al. 2020

Oncol Rep

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Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial-mesenchymal transition by reducing E-cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose-1, 6-biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail-dependent manner. Overexpression of the point-mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild-type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2-IN-1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF-1α and VEGF in HCC cells, but not in FBP1-knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF-1α/VEGF signaling pathways via the Snail-FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease.

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Section: Discussionmentioning

confidence: 51%

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

Fan

Zheng

et al. 2020

Oncol Rep

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“…4 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshedong Road, Zhengzhou 450052, Henan Province, China. 5 Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…HCC usually develops from diverse chronic liver diseases underlying cirrhosis (including chronic viral hepatitis types B and C, alcohol abuse, aflatoxin exposure and nonalcoholic fatty liver disease) [3] and is one of the highly vascularized solid tumors characterized by a high presence of hypervascularity and vascular abnormalities [4]. Antiangiogenic therapy is a vital therapeutic strategy for HCC, especially advanced HCC, and antiangiogenic therapy for the treatment of HCC is well established and accepted [5,6]. However, the initial resistance or development of resistance remains a major problem, and the reason remains unclear [7,8].…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin-2 induces angiogenesis via exosomes in human hepatocellular carcinoma

Xie

Wei

et al. 2020

Cell Commun Signal

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Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is a highly vascularized solid tumor. Angiopoietin-2 (ANGPT2) has been described as an attractive target for antiangiogenic therapy. Exosomes are small extracellular vesicles secreted by most cell types and contribute to cell-to-cell communication by delivering functional cargo to recipient cells. The expression of ANGPT2 in tumor-derived exosomes remains unknown. Methods: We detected the ANGPT2 expression in HCC-derived exosomes by immunoblotting, enzyme-linked immunosorbent assay and immunogold labeling, then observed exosomal ANGPT2 internalization and recycling by confocal laser scanning microscopy, co-immunoprecipitation and immunoblotting. We used two HCC cell lines (Hep3B and MHCC97H) to overexpress ANGPT2 by lentivirus infection or knockdown ANGPT2 by the CRISPR/Cas system, then isolated exosomes to coculture with human umbilical vein endothelial cells (HUVECs) and observed the angiogenesis by Matrigel microtubule formation assay, transwell migration assay, wound healing assay, cell counting kit-8 assay, immunoblotting and in vivo tumorigenesis assay. Results: We found that HCC-derived exosomes carried ANGPT2 and delivered it into HUVECs by exosome endocytosis, this delivery led to a notable increase in angiogenesis by a Tie2-independent pathway. Concomitantly, we observed that HCC cell-secreted exosomal ANGPT2 was recycled by recipient HUVECs and might be reused. In addition, the CRISPR-Cas systems to knock down ANGPT2 significantly inhibited the angiogenesis induced by HCC cell-secreted exosomal ANGPT2, and obviously suppressed the epithelial-mesenchymal transition activation in HCC. Conclusions: Taken together, these results reveal a novel pathway of tumor angiogenesis induced by HCC cellsecreted exosomal ANGPT2 that is different from the classic ANGPT2/Tie2 pathway. This way may be a potential therapeutic target for antiangiogenic therapy.

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“…In the last few years, some of the FDA-approved VEGFR-2 inhibitors, including sorafenib (I), regorafenib (II), lenvatinib (III), nintedanib (IV), sunitinib (V) and pazopanib (VI), were employed for clinical studies either alone or in combination with some other chemotherapies for the treatment of HCC [36]. In 2007, sorafenib (I) was approved by the FDA for the treatment of HCC patients.…”

mentioning

confidence: 99%

Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles

et al. 2020

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In this study, a novel series of 1,2-disubstituted benzo [d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC 50 = 1.98 µM in comparison to sorafenib (IC 50 = 10.99 µM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.

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New Insight into Therapies Targeting Angiogenesis in Hepatocellular Carcinoma

Cited by 43 publications

References 113 publications

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

Angiopoietin-2 induces angiogenesis via exosomes in human hepatocellular carcinoma

Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles

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