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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TL;DR: A promising method to enhance adipogenic effects in the murine subcutis is identified, representing a potential technique for soft tissue reconstruction.
Abstract: Fibroblast growth factor (FGF)-2 induces mitogenesis, angiogenesis and adipogenesis. In this study, the adipogenesis-inducing effects of FGF-2 combined with bilayer artificial dermis in mice were evaluated. FGF-2-impregnated bilayer artificial dermis composed of collagen matrix, PELNAC (Gunze Corp., Osaka, Japan) was implanted subcutaneously into the thoracic region of mice. At 1, 2, 3, and 4 weeks, samples were collected for H&E staining, von Willebrand factor immunostaining, and perilipin immunostaining to examine adipose tissue localization and angiogenesis. The collagen matrix-implanted group without the addition of FGF-2 was prepared as a control. At 2 weeks after the implantation of FGF-2 combined with dermal substitutes, adipocytes appeared in the collagen fibers. At 3–4 weeks, a fat pad was generated with neovascularization. The thickness of the fat pad had significantly increased at 2, 3, and 4 weeks. The remaining collagen was decreased by absorption over time. In the control group, no fat pad was newly formed. This study has identified a promising method to enhance adipogenic effects in the murine subcutis, representing a potential technique for soft tissue reconstruction.
8 citations
TL;DR: The data suggest that signaling molecules other than ERK1/2, AKT1, and p38 MAPK are important mediators for VEGF- and FGF2-stimulated OFPAE cell proliferation after PPP2CA suppression, and suggest that blocking these molecules is not as important as previously thought.
8 citations
Cites background from "Fibroblast growth factors, their re..."
...angiogenesis and production of the potent vasodilator nitric oxide (NO) in placentas, implicating critical roles of VEGF and FGF2 in placental angiogenesis and vasodilatation [5,8–12]....
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Dissertation•
01 Nov 2013
TL;DR: MSCs were found not to reduce the rate of wound closure in the dermal portion of the wound, however they did accelerate re-epithelialisation and this was detectable by OCT.
Abstract: Chronic wounds present a major unmet clinical problem. They arise from wounds that fail to progress through the normal phases of healing due to factors that compound healing such as vascular complications, or diabetes. Despite improvements in treatments for difficult wounds, the incidence of limb amputation remains high. Therefore there is a need for more active therapies.
Mesenchymal stem cells (MSCs) have the capacity to differentiate into multiple cell-types, however they have also been shown to release a plethora of growth factors and cytokines which are beneficial to wound healing, consequently MSCs have shown to improve wound healing outcomes in a predominantly paracrine fashion. MSCs, for example, can increase angiogenesis/ neovascularisation, modulate inflammatory responses, accelerate re-epithelialisation, and increase collagen deposition.
The first objective of the work was to develop a synthetic material based delivery method for MSCs that could be used in the clinic. Plasma polymerisation was used to surface-functionalise medical grade silicone with acrylic acid. The acid surface chemistry enhanced cell attachment to the silicone, and cells could effectively be transferred from the silicone to model wound beds comprised of decellularised dermis (DED). Once the cells were delivered they remained viable, and the acrylic acid surface chemistry was found not to affect the MSC phenotype or their functional capacity prior to cell delivery.
The second part of the project involved developing a 3-D wound model using tissue-engineered (TE) skin, in which to assess the benefit of MSCs, and applying non-invasive imaging to monitor wound healing using optical coherence tomography (OCT). TE skin is reconstructed from DED by the addition of laboratory expanded fibroblasts and keratinocytes, and it possesses a functional epithelium. Full-thickness incisional wounds were created in TE skin, and fibrin clots containing cells could be inserted into the wound cavity; wounds healed after 14 days. OCT could clearly identity structural features of skin (including the dermis, epidermis and fibrin clot) with good correspondence to histology. Appropriate sampling of the wounds by OCT was determined, and consistency in identifying corresponding wound regions within a sample over time was addressed, so that wound volumes could be calculated and compared.
Finally MSCs were introduced to the wound model. MSCs were found not to reduce the rate of wound closure in the dermal portion of the wound, however they did accelerate re-epithelialisation and this was detectable by OCT. Additionally, cytokine analysis was performed on the surrounding medium under wound conditions. In the presence of MSCs, wound medium contained more hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF). Elevated levels of these beneficial factors to wound healing were associated with an early onset of epithelialisation.
8 citations
TL;DR: A review of FGFR2 regulation and function in cancer and its potential as a target for cancer treatment concludes that combination therapy is considered the most promising approach for cancer patients withFGFR2 alterations.
Abstract: Introduction: Fibroblast growth factor receptor 2 (FGFR2) is a highly conserved transmembrane tyrosine kinase receptor. FGFR2 dysregulation occurs in numerous human solid tumors and overexpression is closely associated with tumor progression. FGFR2 has recently been reported as a therapeutic target for cancer. Several targeted therapies are being investigated to disrupt FGFR2 activity; these include multi-target tyrosine kinase inhibitors (TKIs), pan-FGFR targeted TKIs and FGFR2 monoclonal antibodies. Areas: This review examines FGFR2 regulation and function in cancer and its potential as a target for cancer treatment. Expert opinion: Highly specific FGFR2 blockers have not yet been developed and moreover, resistance to FGFR2-targeted therapies is a challenge. More sophisticated patient selection strategies would help improve FGFR2-targeted therapies and combination therapy is considered the most promising approach for cancer patients with FGFR2 alterations.
7 citations
Cites background from "Fibroblast growth factors, their re..."
...Similar to FGFRs, FGFR2 comprises four regions, signal peptide, extracellular region, transmembrane region, and the intracellular region [17,18] (Figure 1)....
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TL;DR: Investigation of the effects of AZD4547 on neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma cells alone and in combination with STAT3 inhibition demonstrated increased efficacy and sensitivity to AZD 4547 appears to be mediated by effects on the Ras/MAPK and JAK/STAT pathways.
Abstract: Children with aggressive pediatric solid tumors have poor outcomes and novel treatments are needed. Pediatric solid tumors demonstrate aberrant expression and activity of the fibroblast growth factor receptor (FGFR) family, suggesting FGFR inhibitors may be effective therapeutic agents. AZD4547 is a multikinase inhibitor of the FGFR1-3 kinases, and we hypothesized that AZD4547 would be effective in pediatric solid tumor preclinical models. We evaluated the effects of AZD4547 on neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma cells alone and in combination with STAT3 inhibition. Continuous live cell imaging was used to measure induction of apoptosis and effects on migration. Receptor inhibition and intracellular signaling were examined by western blotting. AZD4547 treatment resulted in decreased cell confluence, increased apoptosis and reduced cell migration in all tested cell lines. AZD4547 treatment led to decreased phosphorylation of signaling proteins involved in cell survival and apoptotic pathways and increased phosphorylation of STAT3, and treatment of cell lines with AZD4547 combined with STAT3 inhibition demonstrated increased efficacy. Sensitivity to AZD4547 appears to be mediated by effects on the Ras/MAPK and JAK/STAT pathways, and AZD4547 represents a potential novel therapeutic agent for children with solid tumors.
7 citations
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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