Fibroblast growth factors

Fibroblast growth factors (FGFs) are heparin-binding protein mitogens that induce division of most cultured cells derived from embryonic mesoderm and neuroectoderm. Terminally differentiated neurons also respond in vitro by eliciting outgrowth of neurites. In vivo, FGFs have been shown to induce DNA synthesis, cell migration, blood vessel growth, and dermal wound closure. The protein and nucleic acid sequences for two different FGFs, denoted acidic and basic FGF, have been determined and recognized to be homologous. Additional genes recently have been identified that extend this protein family.     

Fibroblast growth factors

Fibroblast growth factors (FGFs) make up a large family of polypeptide growth factors that are found in organisms ranging from nematodes to humans. In vertebrates, the 22 members of the FGF family range in molecular mass from 17 to 34 kDa and share 13-71% amino acid identity. Between vertebrate species, FGFs are highly conserved in both gene structure and amino-acid sequence. FGFs have a high affinity for heparan sulfate proteoglycans and require heparan sulfate to activate one of four cell-surface FGF receptors. During embryonic development, FGFs have diverse roles in regulating cell proliferation, migration and differentiation. In the adult organism, FGFs are homeostatic factors and function in tissue repair and response to injury. When inappropriately expressed, some FGFs can contribute to the pathogenesis of cancer. A subset of the FGF family, expressed in adult tissue, is important for neuronal signal transduction in the central and peripheral nervous systems.     

Fibroblast growth factors and pancreas organogenesis

Fibroblast growth factors (FGFs) are growth factors that regulate many important biological processes, including proliferation and differentiation of embryonic cells during organogenesis. In this review, we have summarized current information about the role of FGFs in pancreas organogenesis. The pancreas organogenesis is a complex process, which involves constant signaling from mesenchymal tissue and activation of various genes regulating particular stages thus determining specification of progenitor cells. Changes in the FGF/FGFR signaling pathway during this process result in incorrect activation of master genes, leading to different pathologies in pancreas development. Understanding the full picture about the role of FGFs in pancreas development will help better understanding of their role in other pathologies of the pancres, including carcinogenesis.     

Fibroblast growth factors in epithelial repair and cytoprotection

Growth factors are polypeptides that stimulate the division of certain cell types at low concentrations. Fibroblast growth factor (FGF) 7 (FGF-7) and its homologue FGF-10 act specifically on various types of epithelial cells including keratinocytes of the skin, intestinal epithelial cells and hepatocytes. In addition, FGF-7 and FGF-10 have been shown to be more than growth factors: they can protect epithelial cells from damaging effects induced, for example, by radiation and oxidative stress. Therefore, they are currently in clinical trials for the treatment of oral mucositis, a severe side-effect of cancer therapy characterized by painful inflammation and ulceration of the oral epithelium. To gain insight into the mechanisms of FGF-7/FGF-10 action in epithelial cells, we searched for genes that are regulated by these growth factors. Indeed, we identified genes that help us to explain the mechanisms that underlie the effects of FGF-7. Most interestingly, several genes were identified that are likely to mediate the cytoprotective effect of FGF-7 for epithelial cells in vitro and possibly also in injured and diseased tissues in vivo.     

Fibroblast growth factors and their receptors in cancer

FGFs (fibroblast growth factors) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration and differentiation during development and adult life. Deregulation of FGFR signalling, on the other hand, has been associated with many developmental syndromes, and with human cancer. In cancer, FGFRs have been found to become overactivated by several mechanisms, including gene amplification, chromosomal translocation and mutations. FGFR alterations are detected in a variety of human cancers, such as breast, bladder, prostate, endometrial and lung cancers, as well as haematological malignancies. Accumulating evidence indicates that FGFs and FGFRs may act in an oncogenic fashion to promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting epithelial-mesenchymal transition, invasion and tumour angiogenesis. Therapeutic strategies targeting FGFs and FGFRs in human cancer are therefore currently being explored. In the present review we will give an overview of FGF signalling, the main FGFR alterations found in human cancer to date, how they may contribute to specific cancer types and strategies for therapeutic intervention.     

Fibroblast growth factor homologous factors are intracellular signaling proteins

Fibroblast growth factors (FGFs) mediate cell growth, differentiation, migration, and morphogenesis by binding to the extracellular domain of cell surface receptors, triggering receptor tyrosine phosphorylation and signal transduction [1-5]. FGF homologous factors (FHFs) were discovered within vertebrate DNA sequence databases by virtue of their sequence similarity to FGFs [3, 6, 7], but the mechanism of FHF action has not been reported. We show here that FHF-1 is associated with the MAP kinase (MAPK) scaffold protein Islet-Brain-2 (IB2) [8] in the brain and in specific cell lines. FHF/IB2 interaction is highly specific, as FHFs do not bind to the related scaffold protein IB1(JIP-1b) [9, 10], nor can FGF-1 bind to IB2. We further show that FHFs enable IB2 to recruit a specific MAPK in transfected cells, and our data suggest that the scaffolds IB1 and IB2 have different MAPK specificities. Hence, FHFs are intracellular components of a tissue-specific protein kinase signaling module.     

Fibroblast growth factors: at the heart of angiogenesis.

Acidic fibroblast growth factor (FGF-1) and basic fibroblast growth factor (FGF-2) are ubiquitous cytokines found in many tissues. They have effects on multiple cell types derived from mesoderm and neuroectoderm, including endothelial cells. In this review the structure and function of the fibroblast growth factor family and its receptors are described. The evidence implicating both FGF-1 and FGF-2 in the control of blood vessel formation is presented and their involvement in normal and pathological angiogenesis during adult life is then described in more detail.     

Fibroblast growth factors in the management of spinal cord injury

Spinal cord injury (SCI) possesses a significant health and economic burden worldwide. Traumatic SCI is a devastating condition that evolves through two successive stages. Throughout each of these stages, disturbances in ionic homeostasis, local oedema, ischaemia, focal haemorrhage, free radicals stress and inflammatory response were observed. Although there are no fully restorative cures available for SCI patients, various molecular, cellular and rehabilitative therapies, such as limiting local inflammation, preventing secondary cell death and enhancing the plasticity of local circuits in the spinal cord, were described. Current preclinical studies have showed that fibroblast growth factors (FGFs) alone or combination therapies utilizing cell transplantation and biomaterial scaffolds are proven effective for treating SCI in animal models. More importantly, some studies further demonstrated a paucity of clinical transfer usage to promote functional recovery of numerous patients with SCI. In this review, we focus on the therapeutic capacity and pitfalls of the FGF family and its clinical application for treating SCI, including the signalling component of the FGF pathway and the role in the central nervous system, the pathophysiology of SCI and the targets for FGF treatment. We also discuss the challenges and potential for the clinical translation of FGF‐based approaches into treatments for SCI.     

Fibroblast growth factors redirect retinal axons in vitro and in vivo

Growth factors have been shown previously to participate in the process of axon target recognition. We showed that fibroblast growth factor receptor (FGFR) signaling is required for Xenopus laevis retinal ganglion cell (RGC) axons to recognize their major midbrain target, the optic tectum [neuron 17 (1996), 245]. Therefore, we have hypothesized that a change in expression of a fibroblast growth factor (FGF) at the entrance of the optic tectum, the border between the diencephalon and mesencephalon, may serve as a signal to RGC axons that they have reached their target. To determine whether RGC axons can sense changes in FGF levels, we asked whether they altered their behavior upon encountering an ectopic source of FGF. We found that in vivo RGC growth cones avoided FGF-misexpressing cells along their path, and that FGF-2 directly repelled RGC growth cones in an in vitro growth cone turning assay. These data support the idea that RGC axons can sense changes in FGF levels, and as such provide a mechanism by which FGFR signaling is involved in RGC axon target recognition.     

Fibroblast growth factors and their receptors in the central nervous system

Fibroblast growth factors (FGFs) and their receptors constitute an elaborate signaling system that participates in many developmental and repair processes of virtually all mammalian tissues. Among the 23 FGF members, ten have been identified in the brain. Four FGF receptors (FGFRs), receptor tyrosine kinases, are known so far. Ligand binding of these receptors greatly depends on the presence of heparan sulfate proteoglycans, which act as low affinity FGFRs. Ligand binding specificity of FGFRs depends on the third extracellular Ig-like domain, which is subject to alternative splicing. Activation of FGFRs triggers several intracellular signaling cascades. These include phosphorylation of src and PLC leading finally to activation of PKC, as well as activation of Crk and Shc. SNT/FRS2 serves as an alternative link of FGFRs to the activation of PKC and, in addition, activates the Ras signaling cascade. In the CNS, FGFs are widely expressed; FGF-2 is predominantly synthesized by astrocytes, whereas other FGF family members, e.g., FGF-5, FGF-8, and FGF-9, are primarily synthesized by neurons. During CNS development FGFs play important roles in neurogenesis, axon growth, and differentiation. In addition, FGFs are major determinants of neuronal survival both during development and during adulthood. Adult neurogenesis depends greatly on FGF-2. Finally, FGF-1 and FGF-2 seem to be involved in the regulation of synaptic plasticity and processes attributed to learning and memory.     

Fibroblast growth factor-2

Fibroblast growth factor-2 (FGF-2) is a member of a large family of proteins that bind heparin and heparan sulfate and modulate the function of a wide range of cell types. FGF-2 stimulates the growth and development of new blood vessels (angiogenesis) that contribute to the pathogenesis of several diseases (i.e. cancer, atherosclerosis), normal wound healing and tissue development. FGF-2 contains a number of basic residues (pI 9.6) and consists of 12 anti-parallel beta-sheets organized into a trigonal pyrimidal structure. FGF-2 binds to four cell surface receptors expressed as a number of splice variants. Many of the biological activities of FGF-2 have been found to depend on its receptor's intrinsic tyrosine kinase activity and second messengers such as the mitogen activated protein kinases. However, considerable evidence suggest that intracellular FGF-2 might have a direct biological role particularly within the nucleus. In addition, heparan sulfate proteoglycans have been demonstrated to enhance and inhibit FGF-2 activity. The possibility that FGF-2 activity can be manipulated through alterations in heparan sulfate-binding is currently being exploited in the development of clinical applications aimed at modulating either endogenous or administered FGF-2 activity.     

Fibroblast growth factor homologous factors: evolution, structure, and function

Fibroblast growth factor homologous factors (FHFs) bear strong sequence and structural similarity to fibroblast growth factors (FGFs). However, the biochemical and functional properties of FHFs are largely, if not totally, unrelated to those of FGFs. Whereas FGFs function through binding to the extracellular domains of FGF receptors (FGFRs), FHFs bind to intracellular domains of voltage-gated sodium channels (VGSCs) and to a neuronal MAP kinase scaffold protein, islet-brain-2 (IB2). These findings demonstrate the remarkable functional adaptability during evolution of the FGF gene family. FHF gene mutations in mice result in a range of neurological abnormalities, and at least one of these anomalies, cerebellar ataxia, is linked to FHF mutations in humans. This article reviews the sequences and structure of FHFs, along with our still limited understanding of FHF function.     

Fibroblast growth factors as regulators of central nervous system development and function

Fibroblast growth factors (FGFs) are multifunctional signaling proteins that regulate developmental processes and adult physiology. Over the last few years, important progress has been made in understanding the function of FGFs in the embryonic and adult central nervous system. In this review, I will first discuss studies showing that FGF signaling is already required during formation of the neural plate. Next, I will describe how FGF signaling centers control growth and patterning of specific brain structures. Finally, I will focus on the function of FGF signaling in the adult brain and in regulating maintenance and repair of damaged neural tissues.     

Fibroblast growth factor-2

Fibroblast growth factor-2 (FGF-2) is a heparin-binding growth factor which occurs in several isoforms resulting from alternative initiations of translation: an 18 kD cytoplasmic isoform and four larger molecular weight nuclear isoforms (22, 22.5, 24 and 34 kD). FGF-2 has pleiotropic roles in many cell types and tissues; it is a motogenic, angiogenic and survival factor which is involved in cell migration, cell differentiation and in a variety of developmental processes. Although devoid of signal peptide, it could be secreted. It acts mainly through a paracrine/autocrine mechanism involving high affinity transmembrane receptors and heparan sulfate proteoglycan low affinity receptors, but also through still unknown intracrine process(es) on intracellular targets. FGF-2 has many biological functions which are probably isoform-specific. Nevertheless, FGF-2 is not essential for embryonic development as knock-out mice for the growth factor are viable and fertile although they exhibit abnormalities in neuronal differentiation. Use of FGF-2 as therapeutic agent for the treatment of ischemic cardiovascular disease is promising and clinical trials are in progress.     

Fibroblast growth factors in myocardial ischemia / reperfusion injury and ischemic preconditioning

Angiogenic growth factors such as fibroblast growth factors (FGFs) are currently in clinical trials for accelerating blood vessel formation in myocardial and limb ischemic conditions. However, recent experimental evidence suggests that FGFs can also participate as endogenous cardioprotective agents. In this report, the current knowledge for FGFs implication in myocardial ischemic tolerance will be summarized. Pharmacologic preconditioning with drugs as FGFs that mimic the beneficial effects of ischemic preconditioning could lead to novel therapeutic approaches for the treatment of ischemic disorders including myocardial infarction and stroke.