Fibroblast growth factor 16 and 18 are expressed in human cardiovascular tissues and induce on endothelial cells migration but not proliferation

Antoine, Marianne; Wirz, W.; Tag, Carmen G.; Gressner, A. M.; Wycislo, M.; Müller, Rebekka; Kiefer, Paul

doi:10.1016/j.bbrc.2006.05.105

Cited by 52 publications

(48 citation statements)

References 28 publications

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“…In addition, FGFs can modulate extracellular matrix degradation, as reported for the capacity of FGF1 and FGF2 to induce the secretion of MMP1 and MMP3 in endothelial cells [44] and the capacity of FGF2 to stimulate the shedding of endothelial membrane vesicles containing MMP1, MMP9 and metalloprotease inhibitors TIMP-1 and TIMP-2 [45]. Also, various studies demonstrate that FGFs promote endothelial cell migration, as shown by the ability of FGF1, FGF2, FGF7, FGF16 and FGF18 to induce a chemotactic response in endothelium [43,46].…”

Section: The Fgf/fgfr System In Endothelial Cellsmentioning

confidence: 83%

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Giacomini

Chiodelli

Matarazzo

et al. 2016

Pharmacological Research

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a b s t r a c tFibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments.The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies.Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop "two-compartment" targeting agents endowed with both antiangiogenic and antitumor activities remains promising.Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer.

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Section: The Fgf/fgfr System In Endothelial Cellsmentioning

confidence: 83%

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Giacomini

Chiodelli

Matarazzo

et al. 2016

Pharmacological Research

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“…Maximal equilibrium binding responses were plotted against the concentrations of FGFR ligand-binding domain, and the equilibrium dissociation constant (K D ) was calculated from the fitted saturation binding curve. The fitted binding curve was judged to be accurate based on the distribution of the residuals (even and near zero) and 2 (Ͻ10% of R max ).…”

Section: Methodsmentioning

confidence: 99%

Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands

Goetz

Ohnishi

Ding

et al. 2012

Molecular and Cellular Biology

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e It has been recently established that Klotho coreceptors associate with fibroblast growth factor (FGF) receptor tyrosine kinases (FGFRs) to enable signaling by endocrine-acting FGFs. However, the molecular interactions leading to FGF-FGFR-Klotho ternary complex formation remain incompletely understood. Here, we show that in contrast to ␣Klotho, ␤Klotho binds its cognate endocrine FGF ligand (FGF19 or FGF21) and FGFR independently through two distinct binding sites. FGF19 and FGF21 use their respective C-terminal tails to bind to a common binding site on ␤Klotho. Importantly, we also show that Klotho coreceptors engage a conserved hydrophobic groove in the immunoglobulin-like domain III (D3) of the "c" splice isoform of FGFR. Intriguingly, this hydrophobic groove is also used by ligands of the paracrine-acting FGF8 subfamily for receptor binding. Based on this binding site overlap, we conclude that while Klotho coreceptors enhance binding affinity of FGFR for endocrine FGFs, they actively suppress binding of FGF8 subfamily ligands to FGFR. Fibroblast growth factor (FGF) signaling plays pleiotropic roles in metazoan development and metabolism (5, 24). Based on sequence homology and phylogenetic and structural considerations, the 18 mammalian FGF ligands are grouped into five paracrine-acting subfamilies and one endocrine-acting subfamily comprising FGF19, FGF21, and FGF23 (24,43). Paracrine FGFs have high affinity for pericellular heparan sulfate (HS) glycosaminoglycans (3, 5) and form distinct morphogenetic gradients in the pericellular matrix (27, 39) to fulfill essential roles during embryonic development (7,24,65). In contrast, endocrine FGFs exhibit poor affinity for HS (3, 15) and thus are able to enter the blood circulation to regulate key metabolic processes, including bile acid homeostasis (18,20,36) and hepatic glucose and protein metabolism (30, 57) (FGF19), glucose and lipid metabolism (4, 21, 29, 58) (FGF21), and vitamin D and phosphate homeostasis (1, 59, 62) (FGF23). These hormone-like FGFs have taken center stage in drug discovery for a number of inherited and acquired metabolic disorders (5, 6).Mammalian FGFs signal through four FGF receptor (FGFR) tyrosine kinases (FGFR1 to FGFR4) and their alternatively spliced isoforms (23, 43). The extracellular domain of a prototypical FGFR consists of three immunoglobulin-like domains (D1 to D3), and structural and biochemical studies have established that the region including D2, D3, and the D2-D3 linker comprises the minimal ligand-binding domain (54,55,63). The ligand-binding specificity of FGFR1 to FGFR3 is primarily regulated by a tissuespecific splicing in D3 of these receptors that generates "b" and "c" isoforms (9,26,42,52). Structural studies have revealed that this splicing alters the primary amino acid sequence of key ligandbinding loops/pockets in D3 (50,74).In addition to mediating paracrine FGF gradient formation in the pericellular matrix, HS is required for enhancing the affinity of paracrine FGF for FGFR and promoting dimerization of ligan...

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“…Despite minimal effects on cellular proliferation (Supplemental Figure 5), ectopic FGF18 overexpression significantly increased cellular migration and invasion of both A224 and OVCA429 cells ( Figure 3C). FGF18 is a member of the FGF family of ligands that have profound effects on blood vessel formation in physiological development (9)(10)(11). To test the potential role of FGF18 in angiogenesis, we investigated the effect of FGF18 on HUVEC motility and tube formation.…”

Section: Fgf18 Confers Oncogenic Effects On Ovarian Cancer Cells In Vmentioning

confidence: 99%

“…Targeted disruption of FGF18 in mice is lethal beyond birth due to impaired skeleton development and alveologenesis, but Fgf1/Fgf2 double-knockout mice are fertile without any gross phenotypic defects (7,8), suggesting unique roles of FGF18 in both embryonic and postnatal development. Acting as a mitogenic, chemotactic, and angiogenic factor, FGF18 is required for the development of bone, cartridge, hair, cardiovasculature, and alveolus (8)(9)(10)(11). Nevertheless, the function of FGF18 has never been studied in the context of serous ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

FGF18 as a prognostic and therapeutic biomarker in ovarian cancer

Wei

Mok²,

Oliva

et al. 2013

J. Clin. Invest.

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High-throughput genomic technologies have identified biomarkers and potential therapeutic targets for ovarian cancer. Comprehensive functional validation studies of the biological and clinical implications of these biomarkers are needed to advance them toward clinical use. Amplification of chromosomal region 5q31-5q35.3 has been used to predict poor prognosis in patients with advanced stage, high-grade serous ovarian cancer. In this study, we further dissected this large amplicon and identified the overexpression of FGF18 as an independent predictive marker for poor clinical outcome in this patient population. Using cell culture and xenograft models, we show that FGF18 signaling promoted tumor progression by modulating the ovarian tumor aggressiveness and microenvironment. FGF18 controlled migration, invasion, and tumorigenicity of ovarian cancer cells through NF-κB activation, which increased the production of oncogenic cytokines and chemokines. This resulted in a tumor microenvironment characterized by enhanced angiogenesis and augmented tumor-associated macrophage infiltration and M2 polarization. Tumors from ovarian cancer patients had increased FGF18 expression levels with microvessel density and M2 macrophage infiltration, confirming our in vitro results. These findings demonstrate that FGF18 is important for a subset of ovarian cancers and may serve as a therapeutic target.

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Fibroblast growth factor 16 and 18 are expressed in human cardiovascular tissues and induce on endothelial cells migration but not proliferation

Cited by 52 publications

References 28 publications

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands

FGF18 as a prognostic and therapeutic biomarker in ovarian cancer

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