Fibroblast growth factors, their receptors and signaling.

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 they can bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs may act directly on target cells, or they can be released through digestion of the ECM or the activity of 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, ultimately resulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most play important roles in embryonic development and wound healing. 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.

The Angiogenic Switch Molecule, Secreted FGF-Binding Protein, an Indicator of Early Stages of Pancreatic and Colorectal Adenocarcinoma

“…The FGF family comprises 23 distinct, structurally-related proteins described to date that exert biologic effects in different cells and organ systems, including tumor growth and angiogenesis (82)(83)(84)(85). FGFs are heparin-binding proteins, which interact with low affinity heparan sulfate proteoglycans (HSPGs).…”

“…HSPGs are ubiquitous cell-surface and extracellular matrix (ECM) proteins, which have been shown to protect FGFs from thermal denaturation and proteolysis as well as to increase FGF receptor affinity and facilitate FGF binding to cell surface receptor. In addition, ECM-associated HSPGs modulate FGF bioavailability by generating a local reservoir for the growth factor and allowing a sustained stimulation of endothelial cells (82,84). Mobilization of FGFs from the ECM storage, and in particular of FGF-1 and FGF-2, occurs via HSPG digestion by heparanases or glycosaminoglycan-degrading enzymes (82,84).…”

FGFR3 mutations in prostate cancer: association with low-grade tumors

“…FGF receptors (FGFR1-4) regulate diverse cellular processes, including cell growth, differentiation, and angiogenesis, and they differ in tissue expression, ligand specificity, signal pathway activation, and biological effects. 12,13 There is a direct causal relationship between the activation of FGFR1 and the angiogenic switch. 14 In prostate tumors, a differential and changing expression of FGFRs has been observed.…”

Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis

“…While the major prognostic determinant is stage at presentation, there is variability in survival for patients with same-stage disease, making it highly advantageous to identify further prognostic markers, which may predict patients likely to benefit from treatment. Furthermore, detecting genes with prognostic relevance has the potential to aid the identification of pathways that may be targeted for therapeutic interventions.The FGF/FGFR receptor (FGFR) signalling pathway plays a pivotal role in cellular biology, being involved in differentiation, angiogenesis and motility (reviewed in Powers et al (2000)). Dysregulation of this pathway is a feature of a number of tumours and allelic imbalance at several FGF/FGFR loci is common in lung cancer.…”

“…The FGF/FGFR receptor (FGFR) signalling pathway plays a pivotal role in cellular biology, being involved in differentiation, angiogenesis and motility (reviewed in Powers et al (2000)). Dysregulation of this pathway is a feature of a number of tumours and allelic imbalance at several FGF/FGFR loci is common in lung cancer.…”