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Journal ArticleDOI

Fibroblast growth factors, their receptors and signaling.

01 Sep 2000-Endocrine-related Cancer (Bioscientifica Ltd)-Vol. 7, Iss: 3, pp 165-197
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 ArticleDOI
TL;DR: It is demonstrated that exogenous kynurenine (KYN) reduces FGF2-mediated expression of alpha-, beta-, and gamma-crystallin and MIP26 in mLEC, and suggests that KYN might inhibit FGF1-mediated fiber cell differentiation by preventing expression of crystallins and Mip26.

1 citations

Journal ArticleDOI
01 Jun 2020
TL;DR: Increased appearance of MMP-2, bFGF in hard tissue of the CLP patients indicates the predominance of tissue degradation and increased number of BMP2/4 positive chondrocytes suggests improved cartilage growth and better regeneration in CLP Patients.
Abstract: Abstract Bone repair after surgical intervention on cleft lip palate (CLP) depends on the coordinated action of multiple tissue regeneration factors. We determined the relative number and appearance of tissue factors: matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), bone morphogenetic protein 2/4 (BMP 2/4), transforming growth factor beta (TGF-ß), Wnt3a protein (Wnt3a), Runt-related transcription factor 2 (Runx2), basic fibroblast growth factor (bFGF) and osteoprotegerin in hard tissue of CLP patients during first time surgical intervention. Fourty-three CLP patients with 24 bone and 36 cartilage samples were involved. Immunohistochemistry was used to assess the levels of tissue factors and the semi-quantitative census method was used for quantification of immunological structures. The increased amount of MMP-2 and bFGF positive cells was detected in the CLP group in cartilage and bone (p < 0.05), compared to the controls. A statistically significant (p = 0.012) increased amount of BMP 2/4 positive cells was found in cartilage of CLP patients, in comparison to the control group. Increased appearance of MMP-2, bFGF in hard tissue of the CLP patients indicates the predominance of tissue degradation. Increased number of BMP2/4 positive chondrocytes suggests improved cartilage growth and better regeneration in CLP patients.

1 citations

01 Jan 2012
TL;DR: In this paper, the authors investigated the effect of Fibroblastenwachstums-faktoren (FGFs) on the Proliferation of ERK1/2 in Ovarialkarzinom.
Abstract: Das Ovarialkarzinom ist eine sich rasch entwickelnde, todliche, aber seltene Erkrankung. Trotzdem ist sie fur 20% aller mit Krebs im Zusammenhang stehenden Todesfalle in den Vereinigten Staaten verantwortlich, da die Krankheit in den meisten Fallen spat diagnostiziert wird. In den letzten Jahrzehnten gab es nur wenig Verbesserung in den therapeutischen Strategien neben der zytotoxischen Therapie und Ovariektomie, aber neue Ergebnisse aus klinischen Studien mit niedermolekularen Inhibitoren der Familie der Rezeptortyrosinkinasen sind sehr vielversprechend. Die Fibroblastenwachstumsfaktoren (FGFs) und ihre Rezeptoren sind involviert in maligne Transformation, Angiogenese und Chemoresistenz und stellen vielversprechende Zielstrukturen in der Krebstherapie dar, insbesondere fur die Uberwindung von Chemoresistenz gegen Zytostatika. Die zugrunde liegenden molekularen Mechanismen wurden allerdings noch nicht erforscht. Das Ziel dieser Arbeit war die Charakterisierung des Signalsystems der Fibroblastenwachstumsfaktoren und sein Einfluss auf Zelleigenschaften im Ovarialkarzinom die mit Malignitat im Zusammenhang stehen. Die Analyse des FGF Rezeptors und seiner Liganden mit RT-PCR ergab, dass die de novo-Expression von FGFs sowie von FGF Rezeptoren im Ovarialkarzinom haufig zu finden ist (70%) und zu autokrinen Signalschleifen mit hohem mitogenen Potential fuhrt. Wie durch Immunoblotting gezeigt wurde, ist das Signalsystem in diesen Zellen funktionell, und konditioniertes Wachstumsmedium war unterschiedlich stark in der Lage, die Phosphorylierung von ERK1/2 zu induzieren. Wachstumsassays zeigten eine signifikante Steigerung der Proliferation bei der Behandlung mit FGF-2 in 50% der untersuchten Zelllinien. FGF-1 zeigte eine nicht-signifikante Steigerung der Motilitat in 66% dieser Zellen. Die Abhangigkeit von Ovarialkarzinomzellen von Signalen der FGF Rezeptoren wurde durch Wachstumsinhibierungsassays untersucht. Dabei wurden zwei unterschiedliche, niedermolekulare Inhibitoren verwendet – PD173074, ein spezifischer Inhibitor der FGF Rezeptorfamilie und Dovitinib (CHIR-258), ein Inhibitor mit geringerer Spezifitat fur einzelne Rezeptoren aber mit hoherer Bandbreite. A-2780 Zellen zeigten eine extrem hohe Sensitivitat gegen FGFR-Inhibierung, wahrend HEY und SKOV-3 Zellen eine moderate Sensitivitat aufwiesen. OVCAR-3 Zellen zeigten eine hohe Resistenz gegenuber der Inhibierung von Rezeptortyrosinkinasen der Klassen III, IV und V. Zusammen zeigen diese Daten, dass Inhibitoren der FGF Rezeptoren ein gutes Potential in der Behandlung des Ovarialkarzinoms haben, moglicherweise aber noch mehr in Kombination mit Zytostatika. Allerdings unterstreicht die starke Varianz in der Reaktion der unterschiedlichen Zellen auf die FGFR-Inhibierung die Notwendigkeit zuverlassiger Serummarker um die therapeutischen Strategien fur die Behandlung des Ovarialkarzinoms zu verbessern.

1 citations


Cites background from "Fibroblast growth factors, their re..."

  • ...FGF signaling is crucial for the development of almost all t issues and organs (Powers et al 2000) as well as homeostasis in adult body t issues, leading to pathological condit ions, cell t ransformation and cancer when normal FGFR functions or expression levels are altered....

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16 Apr 2014

1 citations


Cites background from "Fibroblast growth factors, their re..."

  • ...Two major signaling cascades include MAPK and PI3K cascades[42, 43]....

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References
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Journal ArticleDOI
22 Feb 1991-Cell
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

Journal ArticleDOI
16 Feb 1995-Nature
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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Journal ArticleDOI
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

Journal ArticleDOI
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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Journal ArticleDOI

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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