Fibroblast growth factors, their receptors and signaling.
TL;DR: FGF signaling also appears to play a role in tumor growth and angiogenesis, and autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state.
Abstract: Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides for secretion and are secreted into the extracellular environment, where theycan bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs mayact directlyon target cells, or theycan be released through digestion of the ECM or the activityof a carrier protein, a secreted FGF binding protein. FGFs bind specific receptor tyrosine kinases in the context of HLGAGs and this binding induces receptor dimerization and activation, ultimatelyresulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most playimportant roles in embry onic development and wound healing. FGF signaling also appears to playa role in tumor growth and angiogenesis, and autocrine FGF signaling maybe particularlyimportant in the progression of steroid hormone-dependent cancers to a hormone-independent state.
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Journal Article•
TL;DR: Valdecoxib inhibited LPS-induced proliferation of endothelial cells and bFGF secretion in a dose-dependent manner and stimulated VEGF formation via HMEC-1 under inflammatory conditions.
Abstract: Background Endothelial cells produce prostaglandins (PGE2 and PGI2) and growth factors (VEGF and bFGF). These substances regulate proliferation of cells, inflammatory processes and neovascularization under physiological and pathological conditions. Objectives The aim of this study was to check whether valdecoxib - a selective COX-2 inhibitor - inhibits VEGF and/or bFGF secretion in the presence of LPS or cobalt chloride in normal human microvascular endothelial cells (HMEC-1). Material and methods HMEC-1 cells were treated with valdecoxib at a concentration of 10 and 100 μM in the presence of 100 μg/mL LPS or 200 μM CoCl2. The effect of NSAIDs and LPS on VEGF and bFGF proteins was analyzed by ELISA kit (R&D Systems). Cell viability was measured using the 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) method. Results Valdecoxib inhibited LPS-induced proliferation of endothelial cells and bFGF secretion in a dose-dependent manner. Valdecoxib stimulated VEGF formation via HMEC-1 under inflammatory conditions.
6 citations
01 Jan 2009
TL;DR: The mammalian ovary is a dynamic organ that provides an ideal environment for the production of hormones and release of the female gamete.
Abstract: The mammalian ovary is a dynamic organ that provides an ideal environment for the production of hormones and release of the female gamete. The ovary contains thousands of ovarian follicles which are its basic structural and functional unit. The ovarian folliculogenesis is a complex process that consists of the development of primordial follicles to the stage of preovulatory follicle, occurring oocyte growth and intense proliferation of the granulosa cells during this period. Several growth factors produced by follicular cells often act by modulating the effects of gonadotrophins FSH and LH, controlling thus folliculogenesis. In this review will discuss the localization and in vitro effects of growth factors, such as epidermal growth factor (EGF), fibroblastic growth factor (FGF), insulin-like growth factor (IGF) transforming growth factor-s (TGF-s) and Kit ligand (KL) in the control of follicular development. Some of these growth factors, such as EGF, FGF, IGF, TGF-s, BMP-2, -4, -6, -7, -15, GDF-9, activin-A and KL stimulate the development of ovarian follicles and are involved in the control of steroidogenesis and follicular atresia. On the other hand, a few factors, like inhibin, exert an inhibitory action on the secretion of gonadotropins and control the effect of FSH in the ovary.
6 citations
TL;DR: Investigating the relation between the serum level of FGF21 with and metabolic syndrome (MS) in kidney transplant recipients revealed that serum FGF 21 levels were not significantly increased in renal transplanted recipients with MS as compared with non-MS group.
Abstract: Introduction: Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple beneficial effects on glucose and lipid homeostasis and insulin sensitivity. Objectives: The aim of this study was to investigate the relation between the serum level of FGF21 with and metabolic syndrome (MS) in kidney transplant recipients. Patients and Methods: We performed a cross-sectional study on 86 stable renal transplant recipients to detect possible relation between serum FGF21 level and MS during October 2014 and Mach 2015. Patients with past history of diabetes mellitus were excluded. Results: There were 43 patients in each group with and without MS. Totally, they were 52 (60.5%) male and 34 (39.5%) female. The mean age of the MS group was significantly higher than that of non-MS group. There was not significant difference between mean serum creatinine level and glomerular filtration rate (GFR) between two groups (P > 0.05). The MS patients had higher weight and body mass index (BMI) (P 25 kg/m2 in MS group was 25 (58.8%) versus non-MS group that only 10 (23.3%) had this condition (P 0.05). There was not significant difference of serum FGF21 level between MS and non-MS patients (P > 0.05). Conclusion: While the elevated serum FGF21 level was found in subjects with insulin resistant states, however, this study revealed that serum FGF21 levels were not significantly increased in renal transplanted recipients with MS as compared with non-MS group.
6 citations
Cites background from "Fibroblast growth factors, their re..."
...Human FGF21 is a polypeptide of 181 amino acids produced predominantly by the liver (3)....
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...Introduction The fibroblast growth factor (FGF) family is composed of 22 members with a wide range of biological functions including cell growth, development, angiogenesis, and wound healing (1-5)....
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TL;DR: In this article, a review highlights the similarities and differences between GSCs and SVZ NSCs in terms of their gene expression, regulatory molecular pathways, niche organization, metabolic programs and current therapies designed to exploit these differences.
Abstract: During embryonic development, radial glial precursor cells give rise to neural lineages, and a small proportion persist in the adult mammalian brain to contribute to long-term neuroplasticity. Neural stem cells (NSCs) reside in two neurogenic niches of the adult brain, the hippocampus and the subventricular zone (SVZ). NSCs in the SVZ are endowed with the defining stem cell properties of self-renewal and multipotent differentiation, which are maintained by intrinsic cellular programs, and extrinsic cellular and niche-specific interactions. In glioblastoma, the most aggressive primary malignant brain cancer, a subpopulation of cells termed glioblastoma stem cells (GSCs) exhibit similar stem-like properties. While there is an extensive overlap between NSCs and GSCs in function, distinct genetic profiles, transcriptional programs, and external environmental cues influence their divergent behavior. This review highlights the similarities and differences between GSCs and SVZ NSCs in terms of their gene expression, regulatory molecular pathways, niche organization, metabolic programs, and current therapies designed to exploit these differences.
6 citations
Dissertation•
01 Jan 2014
TL;DR: The hypothesis that FGFR3 activation can play a causative role in urothelial pathogenesis of non-invasive superficial bladder cancer together with upregulated PI3K-AKT signalling is supported.
Abstract: Bladder cancer is the 5th most common and the 9th most lethal cancer in the UK. Based on histopathological and genomic analysis, a model of two independent pathogenesis pathways has been suggested, resulting in either non-invasive superficial or invasive urothelial tumours with potential to metastasise. Prominently, the fibroblast growth factor receptor 3 (FGFR3) is found mutated in up to 84% of non-invasive superficial tumours. Alterations in FGFR3 such as mutation or wild type receptor overexpression are also found in 54% of muscle-invasive tumours. FGFR3 is a tyrosine kinase receptor for fibroblast growth factors (FGFs), which stimulates both the RAS/MAPK and the PI3K/AKT pathways and regulates a range of cellular processes such as cell growth and division during development. In this study we examined the role of FGFR3 in bladder cancer by using mice as a model organism.
Firstly, we addressed whether combination of Fgfr3 and Pten mutation, UroIICre Fgfr3+/K644E Ptenflox/flox, is able to drive non-invasive superficial bladder cancer. We observed that the thickness of the double mutant urothelium was significantly increased compared to singly mutated Fgfr3 or Pten, UroIICre Fgfr3+/K644E and UroIICre Ptenflox/flox. Moreover, several cellular abnormalities were detected that were accompanied by differential expression of layer-specific markers, which strongly suggested that they were caused cooperatively by Fgfr3 mutation and Pten deletion. The results supported the hypothesis that FGFR3 activation can play a causative role in urothelial pathogenesis of non-invasive superficial bladder cancer together with upregulated PI3K-AKT signalling.
Secondly, we aimed to identify mutations that cooperate with Fgfr3 and with other common bladder cancer mutations such as Pten and Ras, in promoting urothelial tumourigenesis by Sleeping Beauty (SB) insertional mutagenesis in mice. The SB system may constitute an inefficient tool in the bladder to induce urothelial tumourigenesis, since it failed to produce bladder tumours in Fgfr3 as well as in Hras mutant mice. In mice with Pten deletion, one tumour was generated and general hypertrophy with cellular abnormalities was observed in all samples. No direct association between Fgfr3 and Pten mutations was found; however, SB mutagenesis supported that Fgfr3 and Pten cooperation may merge at the signalling downstream.
Thirdly, we examined the role of the most common mutation in FGFR3, S249C, in the urothelium and in tumour progression and invasion by subjecting Fgfr3 mutant mice to a bladder-specific carcinogen, N-butyl-N-(hydroxybutyl)-nitrosamine (OH-BBN). We showed that FGFR3 S249C mutation by itself does not lead to urothelial abnormalities. However, in OH-BBN-induced tumours the presence of S249C increased the number of animals that formed bladder tumours by 4.4-fold. Our results present for the first time an effect of FGFR3 S249C mutation in invasive bladder cancer.
Lastly, we sought to establish methods to generate and assess invasive bladder tumours using in vivo and in vitro techniques. First we examined the effectiveness of a Cre-expressing adenovirus (AdenoCre) to generate mouse models of bladder cancer with different combinations of genetic mutations. p53 deletion or mutation together with Pten loss led to formation of aggressive bladder tumours; however the origin of these tumours was likely to be the bladder muscle. Hras activation in combination with Pten deletion did not produce tumours or any cellular abnormalities by 8 months. AdenoCre-mediated tumour induction was successful in the presence of β-catenin and Hras mutation. However, an issue of AdenoCre transduction was the frequent observation of tumours in various other tissues such as the pelvic soft tissue, liver, pancreas and lung. Using an optimised AdenoCre procedure, the technique would allow lineage tracing of cancer stem cells in a developing bladder tumour and potentially during metastatic spread. Secondly, we tested imaging techniques in the living animals and validated ultrasound as a functional method to detect bladder wall thickening, as well as to monitor tumour growth in vivo. Thirdly, with the aim to assess cell transformation, migration and response to drug treatment, we tested essential ex vivo techniques and assays such as 3D sphere culture, organotypic slice culture as well as a Collagen-I invasion assay. The 3D tumour sphere culture was successful with murine Wnt-activated tumours as well as with invasive human cell lines. The organotypic slice culture was assessed as a system to test the effect of therapeutic drugs on the tumour cells; however, an issue of tissue disintegration has yet to be overcome. The Collagen-I assay successfully recapitulated invasion of a human bladder cancer cell line; however, the system needs to be adapted to murine bladder tumours.
Taken together, this study presents for the first time evidence that support the functional role of FGFR3 signalling in the early stages of non-invasive urothelial carcinoma as well as in tumour progression of established neoplasms in mice. Given the wide availability of inhibitors specific to FGF signalling, our FGFR3 mouse models in conjunction with optimised ex vivo assays and imaging systems may open the avenue for FGFR3-targeted translation in urothelial disease.
6 citations
Cites background from "Fibroblast growth factors, their re..."
...FGFR3 is known to be activated by FGF1, FGF2, FGF8, FGF9, and FGF18; and FGFR4 can bind to FGF 1, FGF 2, FGF 4, FGF 6, FGF8 and FGF 9 (Powers et al., 2000, Davidson et al., 2005)....
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...Upregulation of FGF1, FGF2, FGF6, FGF7, FGF8 and FGF9 levels are detectable in prostate cancer (Kwabi-Addo et al., 2004)....
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...FGFR3IIIb for example shows higher affinity for FGF1 (aFGF) and FGF7 (KGF), but a lower affinity for FGF8 and FGF9, while FGFR3IIIc binds FGF1, FGF2, FGF4, FGF8 and FGF9 (Chellaiah et al., 1994, Ahmad et al., 2012a)....
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...FGFR1 is known to bind FGF1 (acidic-FGF, aFGF), FGF2 (basic-FGF, bFGF), FGF3, FGF4, FGF5, FGF6, FGF8 and FGF10; FGFR2 can additionally bind FGF7 and FGF9 (Powers et al., 2000)....
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References
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TL;DR: It is demonstrated that free heparin and heparan sulfate can reconstitute a low affinity receptor that is, in turn, required for the high affinity binding of bFGF.
2,448 citations
TL;DR: This work highlights conserved protein domains that act as key regulatory participants in many of these different signalling pathways in multicellular organisms.
Abstract: Communication between cells assumes particular importance in multicellular organisms. The growth, migration and differentiation of cells in the embryo, and their organization into specific tissues, depend on signals transmitted from one cell to another. In the adult, cell signalling orchestrates normal cellular behaviour and responses to wounding and infection. The consequences of breakdowns in this signalling underlie cancer, diabetes and disorders of the immune and cardiovascular systems. Conserved protein domains that act as key regulatory participants in many of these different signalling pathways are highlighted.
2,433 citations
"Fibroblast growth factors, their re..." refers background in this paper
...One way these recruited target proteins may be localized to the activated receptor is through the interaction between their Src-homology 2 (SH2) domains and specific phosphotyrosine residues on the activated receptor (Pawson 1995)....
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...Phosphorylated tyrosine residues, in turn, recruit other signaling molecules to the activated receptors and propagate the signal through many possible transduction pathways (Pawson 1995)....
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TL;DR: Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of Thalidomid-treated embryos.
Abstract: Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.
2,364 citations
TL;DR: It is demonstrated that FGF 1 is the only FGF that can activate all FGF receptor splice variants and the relative activity of all the other members of the FGF family is determined.
2,066 citations
"Fibroblast growth factors, their re..." refers background in this paper
...†From Ornitz et al. (1996), except where stated; ‡From Koga et al. (1995); §From Miralles et al. (1999); ¶From Xu et al. (1999). topologically identical to interleukin-1β (IL-1β) (Zhu et al. 1991), with which some members also share the feature of secretion by an endoplasmic reticulum…...
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...Mutation of all four cysteines to serines results in a protein with the same secondary structure and equally mitogenic for 3T3 cells as the wild-type FGF-2 (Foxet al. 1988), suggesting that the formation of disulfide bridges is not important for the secondary structure and mitogenic activity of…...
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...Ornitz et al. (1996) determined the specificity of different FGFs for different receptor isoforms by overexpressing these isoforms in Baf3 cells, which do not normally express FGFRs, and assaying for [3H]thymidine incorporation in these cells following treatment with different FGFs (see Table 2)....
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...1, IIIb 100 60 34 16 4 5 6 4 4 1, IIIc 100 104 0 102 59 55 0 1 21 2, IIIb 100 9 45 15 5 5 81 4 7 2, IIIc 100 64 4 94 25 61 2.5 16 89 3, IIIb 100 1 2 1 1 1 1 1 42 3, IIIc 100 107 1 69 12 9 1 41 96 4 100 113 6 108 7 79 2 76 75 Modified from Ornitz et al. (1996)....
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1,994 citations
"Fibroblast growth factors, their re..." refers background in this paper
...Defining features of the FGF family are a strong affinity for heparin and HLGAGs (Burgess & Maciag 1989), as well as a central core of 140 amino acids that is highly homologous between different family members....
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