An FGF8b-mimicking peptide with potent antiangiogenic activity

Abstract

Fibroblast growth factor (FGF) 8b interacts with its receptors and promotes angiogenesis in hormone‑dependent tumors. In the present study, we demonstrated that a short peptide, termed 8b‑13, which mimics part of the FGF8b structure, significantly inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVECs) triggered by FGF8b using 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT), flow cytometry and an in vitro scratch assay. In addition, the findings from western blotting and reverse transcription‑quantitative polymerase chain reaction revealed that 8b‑13 appeared to counteract the effects of FGF8b on the expression of cyclin D1, the activation of signaling cascades, and the expression of proangiogenic factors; these actions may be involved in the mechanism underlying the inhibitory effects of 8b‑13 on FGF8b‑induced HUVEC proliferation and migration. The present results suggested that 8b‑13 may be considered a potent FGF8b antagonist with antiangiogenic activity, and may have potential as a novel therapeutic agent for the treatment of cancer characterized by abnormal FGF8b upregulation.

New developments in the biology of fibroblast growth factors

“…Inhibitory peptides can also be derived directly from ligand sequences. A 13 amino acid peptide that mimics part of FGF8b inhibited the proliferation of prostate cancer cells and the proliferation and migration of human umbilical vein endothelial cells (HUVECs) (Li et al, 2013; Lin et al, 2017). When injected intracerebroventricularly (third ventricle), this peptide inhibited endocrine FGF signaling (FGFs 15/19 and 21) and improved glucose tolerance (S. Liu, Marcelin, et al, 2018).…”

Immunoreactivity against fibroblast growth factor 8 in alveolar rhabdomyosarcoma patients and its involvement in tumor aggressiveness

“… 23 , 56 Moreover, FGF8 induces the expression of PLAU gene in HUVEC cells, 60 that encodes the urokinase-type plasminogen activator (uPA) which plays a major role in tumor progression and metastasis in several cancers, besides in promoting angiogenesis and influencing immune response mechanisms. 61–63 In all these cases, FGF8 acts by linking cell surface receptors and receptor substrates to downstream signal transduction pathways MEK/ERK, PI3K/AKT or STAT/JAK, in a paracrine/autocrine manner that can be prevented by either receptor inhibition, ligand trapping, or neutralizing antibodies treatment. 64–66 Recently, autocrine/paracrine mechanisms have been described for FGF18/FGFR2 and FGF19/FGFR4 axis in gastric cancer and hepatocellular carcinoma, respectively, and clinical trials contemplating the administration of FGFR drug inhibitors have been proposed.…”

Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis

“…While these peptides also block FGF2, they show higher affinity for FGF8b. In particular, FGF8b inhibition by ARPCA decreased HUVECs migration and sprouting, and resulted in reduced proliferation and vascularization of androgen-dependent mouse mammary tumors implanted into the flank of nude mice [203,204].…”

“…-Intravenous delivery of autologous T cells, modified to recognize CD44v6 on the surface of cancer cells (ClinicalTrials.gov: NCT04427449 [95]). -Monoclonal antibodies against FGF8b [202]; using natural inhibitor Pentraxin-3 (PTX3) and its derivatives Ac-ARPCA-NH2 (ARPCA) and 8b-13 [203,204] to target FGFs.…”