Abstract
Angiogenesis is a fundamental developmental process and a hallmark of cancer progression. Receptor tyrosine kinases (RTK) are targets for cancer therapy which may include their action as anti-angiogenic agents. Derazantinib (DZB) is an inhibitor of the fibroblast growth factor receptors (FGFRs) 1–3 as well as other kinase targets including vascular endothelial growth factor receptor 2 (VEGFR2), colony stimulating factor-1 receptor (CSF1R) and platelet-derived growth factor beta receptor (PDGFRbeta). This study aimed to investigate the effect of DZB on blood vessel morphogenesis and to compare its activity to known specific FGFR and VEGFR inhibitors. For this purpose, we used the developing vasculature in the zebrafish embryo as a model system for angiogenesis in vivo. We show that DZB interferes with multiple angiogenic processes that are linked to FGF and VEGF signalling, revealing a potential dual role for DZB as a potent anti-angiogenic treatment.
Highlights
Angiogenesis is a physiological process in which new blood vessels are formed from pre-existing vessels [1]
We found that blood flow in larger vessels, i.e., within the dorsal aorta (DA) or the posterior cardinal vein (PCV), appeared normal in zebrafish embryos treated with DZB
These findings suggest that both DZB and infigratinib inhibit cell cycle progression potentially via fibroblast growth factor receptors (FGFRs) signalling during vascular development
Summary
Angiogenesis is a physiological process in which new blood vessels are formed from pre-existing vessels [1]. Angiogenesis occurs during normal growth and development, and under physiological conditions, and is tightly regulated by the coordinated actions of both anti-angiogenic [2] and pro-angiogenic factors, of which the latter include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) and their respective receptors [3]. Tumor angiogenesis is one of the hallmarks of cancer and plays a crucial role in providing oxygen and nutrients to tumor cells during cancer progression and metastasis. Disruption of this process has been a major area of research which has led to a number of useful clinical treatments including bevacizumab, aflibercept, ramucirumab and small-molecule VEGFR inhibitors such as sunitinib and vatalanib [3,4]. The most effective combination may be when a relatively weak anti-angiogenic effect is employed since this results in a greater immune infiltration [8]
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