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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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01 Jan 2006
TL;DR: Platelet-derived endothelial cell growth-factor (PDECGF) is similar to the pyrimidine enzyme thymidine phosphorylase (TP) and hence plays a dual role in cell biology and is related to malignant angiogenesis and invasion, and is therefore associated with a poor prognosis.
Abstract: Summary Platelet-derived endothelial cell growth-factor (PDECGF) is similar to the pyrimidine enzyme thymidine phosphorylase (TP) and hence plays a dual role in cell biology. A high expression is related to malignant angiogenesis and invasion, and is therefore associated with a poor prognosis. It has been postulated that the angiogenic effect of PDECGF/TP is related to the enzymatic activity of TP, which catalyzes the breakdown of thymidine to thymine and deoxyribose-1-phosphate (dR-1-P). The latter, in its parent form or in its sugar form, deoxyribose, may play a role in angiogenesis. It may interfere in cellular energy metabolism or be substrate in a chemical reaction generating reactive oxygen species. L-deoxyribose and a specific TP inhibitor, TPI, can reverse these effects, supporting the role of the enzymatic reaction and that of the sugar. The essential role of TP in cellular metabolism was demonstrated by the finding that a deficiency was associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), which is an autosomal, recessive disorder involving mitochondrial DNA alterations. This syndrome was not associated with abnormal vascularization, indicating that TP/PDECGF only plays a role in malignant angiogenesis. Besides the role in angiogenesis, TP also plays an important role in thymidine homeostasis and thus in the synthesis of TMP a precursor in DNA synthesis. A high TP may deplete thymidine and its nucleotides. TP has a also an important pharmacological action. It has a moderate or even negligible role in the activation of the antimetabolite 5-fluorouracil (5FU), but its phosphorolytic activity is essential for the activation of 5’-deoxyfluorouridine (5DFUR) to 5FU. 5DFUR is an intermediate in the activation of the oral 5FU prodrug Capecitabine (Xeloda). Since the expression of TP/PDECGF is high in solid tumors and its stroma, this may be responsible for selective activation of 5DFUR in tumor cells. Since TP is easily inducible by external signals, e.g. radiation, cytokine exposure (tumor necrosis factor, interleukin, interferon), or cytotoxics (e.g.

24 citations

Journal ArticleDOI
TL;DR: The effect of astaxanthin, which is a strong antioxidant, on the regulation of oxidative stress and scarring during vocal fold wound healing is investigated.
Abstract: Objectives/Hypothesis Our previous study demonstrated that a large amount of reactive oxygen species (ROS) is produced during the early phase of vocal fold wound healing. In the current study, we investigated the effect of astaxanthin, which is a strong antioxidant, on the regulation of oxidative stress and scarring during vocal fold wound healing. Study Design Prospective animal experiment with control. Methods Sprague-Dawley rats were dosed with astaxanthin (Ast-treated group, 100 mg/kg/day) or olive oil (sham-treated group) by oral gavage daily from preinjury day 1 to postinjury day 4. After vocal folds were injured under the endoscope, larynges were harvested for histological and immunohistochemical examinations on postinjury days 1, 3, 5, and 56, and quantitative real time polymerase chain reaction (PCR) on postinjury days 1 and 3. Results The expression of 4-hydroxy-2-nonenal, which is an oxidative stress marker, was reduced significantly in the lamina propria of the Ast-treated group as compared to the sham-treated group. Histological examination showed significantly less tissue contraction with favorable deposition of hyaluronic acid in the lamina propria of the Ast-treated group compared to the sham-treated group. Real time PCR revealed significantly upregulated mRNA expression of basic fibroblast growth factor on postinjury day 1 and procollagen type I in the Ast-treated group compared to the sham-treated group. Conclusions These findings suggest that astaxanthin has the potential to prevent vocal fold scarring by regulating oxidative stress during the early phase of vocal fold wound healing. Level of Evidence: NA Laryngoscope, 124:E1–E7, 2014

24 citations


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

  • ...In particular, bFGF plays a role in granulation tissue formation, epithelialization, and tissue remodeling.(30,31) In addition, bFGF was reported to improve acute vocal scars....

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Journal ArticleDOI
TL;DR: It is demonstrated that FGF-10 maintains the morphological integrity of goat preantral follicles and stimulates the growth of activated follicles in culture.

24 citations


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

  • ...The fibroblast growth factor (FGF) family constiutes one of the most important groups of paracrine actors that act during cell development [1] and consists f at least 23 different signaling polypeptide members 2]....

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  • ...[1] Powers CJ, Mcleskey SW, Wellstein A....

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Journal ArticleDOI
TL;DR: Mechanistic studies found that bFGF was upregulated in osteoblasts from PC3-injected tibiae of Tgfbr2Col1CreERT KO mice and correlated with increased tumor cell proliferation, angiogenesis, amounts of cancer-associated fibroblasts and osteoclasts, suggesting bF GF is a promising target inhibiting bone metastasis.

24 citations

Journal ArticleDOI
TL;DR: It is proposed that the upregulation of the secreted FGF-BP protein during early phases of pancreas and colon cancer could make this protein a possible serum marker indicating the presence of high-risk premalignant lesions.
Abstract: Tumor angiogenesis has been related to the initiation as well as progression toward more aggressive behavior of human tumors. In particular, the activity of angiogenic factors is crucial for tumor progression. We previously characterized a secreted fibroblast growth factor-binding protein (FGF-BP) as a chaperone molecule, which binds to various FGFs, enhances FGF-mediated biochemical and biologic events and importantly is a crucial rate-limiting factor for tumor-dependent angiogenesis. We generated monoclonal antibodies that target FGF-BP protein and used them as a tool to evaluate frequency and pattern of FGF-BP expression during the malignant progression of pancreas and colorectal carcinoma in archival tissue samples. We found that FGF-BP is dramatically upregulated during the initiation of colorectal and pancreatic adenocarcinoma. Crucial genetic events underlying the initiation and progression of colorectal and pancreatic adenocarcinoma with a particular focus on the modulation of angiogenesis and antiangiogenic therapies are discussed. We propose that the upregulation of the secreted FGF-BP protein during early phases of pancreas and colon cancer could make this protein a possible serum marker indicating the presence of high-risk premalignant lesions. Furthermore, the biological activity of FGF-BP is neutralized by monoclonal antibodies suggesting the potential for antibody-based therapeutic targeting.

24 citations

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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