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: Although it is found no evidence supporting a “two‐hit” inactivation of FGFRL1 in bladder carcinogenesis, the effect of heterozygous deletion coupled with functional polymorphisms, and the role of post‐transcriptional downregulation deserves further investigation.
Abstract: Loss of heterozygosity (LOH) of chromosome arm 4p is a common event in bladder and other malignancies. At least three distinct regions of deletion have been identified, but the deletion targets have so far remained elusive. In this study, we have identified a novel region of deletion mapping to 4p16.3 spanning 0-2.1 Mb, in 15% of bladder tumors and 24% of bladder cancer cell lines. FGFRL1, which maps within this region, was investigated as putative deletion target. The retained FGFRL1 allele was not mutated in cell lines and tumors with LOH, although in patients heterozygous for the rs4647930 functional polymorphism, the common allele was preferentially lost in tumor tissue. Epigenetic silencing of the retained allele was also excluded as levels of FGFRL1 mRNA and protein were similar in cell lines and tumors with and without 4p16.3 loss. However, while FGFRL1 protein was moderately expressed in all layers of the normal bladder epithelium, the majority of tumors showed areas of downregulation. Overall, average FGFRL1 protein expression was significantly lower in bladder tumors compared to normal tissue, but downregulation was independent from 4p16.3 LOH status, FGFR3 mutation, and tumor grade and stage. In conclusion, although we found no evidence supporting a "two-hit" inactivation of FGFRL1 in bladder carcinogenesis, the effect of heterozygous deletion coupled with functional polymorphisms, and the role of post-transcriptional downregulation deserves further investigation.
14 citations
Cites background from "Fibroblast growth factors, their re..."
...FGFRs are trans-membrane tyrosine-kinase receptors mediating the cellular effects of fibroblast growth factors (FGFs) (Powers et al., 2000)....
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...FGFRs1–4 are composed of an extracellular domain with specificity for binding FGFs and heparan sulphate proteoglycans, a transmembrane domain, and an intracellular split tyrosine-kinase domain (Powers et al., 2000)....
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...heparan sulphate proteoglycans, a transmembrane domain, and an intracellular split tyrosine-kinase domain (Powers et al., 2000)....
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TL;DR: Differences in 3-year overall survival values of patients with bone sarcomas with different initial serum levels of FGF-1 and endostatin were detected, and a significant relationship between serum PlGF level and maximum tumor size was detected in osteosarcoma.
Abstract: Serum levels of endostatin, placental growth factor (PlGF), and fibroblast growth factors-1 and -2 (FGF-1 and FGF-2) were measured in 58 patients with primary osteosarcomas before therapy and in 21 healthy subjects. The incidence of serum FGF-1 in bone tumors was 2.5 times higher than in healthy individuals (p=0.004); significant levels of FGF-2, PlGF, and endostatin were detected in all examined subjects. The mean serum level of endostatin in healthy individuals was significantly lower than in the total group of patients with bone tumors (p=0.005). The level of FGF-1 in osteosarcomas was significantly higher than in chondrosarcomas (p<0.05). No appreciable differences in FGF-2 levels were detected in patients with tumors of different histological structure. The mean serum content of PlGF was virtually the same in healthy individuals and patients with bone tumors. A significant relationship between serum PlGF level and maximum tumor size (p=0.008) was detected in osteosarcoma. No relationships between the levels of FGF-1, FGF-2, PlGF, and endostatin were detected in healthy subjects and patients with primary tumors of the bones. Differences in 3-year overall survival values of patients with bone sarcomas with different initial serum levels of FGF-1 and endostatin were detected.
14 citations
TL;DR: It is demonstrated that loss of Notch signaling by conditional deletion of Rbpj in the hypothalamus does not affect expression of Hes1 within the posterior hypothalamus orexpression of Hes5, which is sufficient to disrupt pituitary development and postnatal expansion.
Abstract: Background: As the pituitary gland develops, signals from the hypothalamus are necessary for pituitary induction and expansion. Little is known about the control of cues that regulate early signaling between the two structures. Ligands and receptors of the Notch signaling pathway are found in both the hypothalamus and Rathke's pouch. The downstream Notch effector gene Hes1 is required for proper pituitary formation; however, these effects could be due to the action of Hes1 in the hypothalamus, Rathke's pouch, or both. To determine the contribution of hypothalamic Notch signaling to pituitary organogenesis, we used mice with loss and gain of Notch function within the developing hypothalamus. Results: We demonstrate that loss of Notch signaling by conditional deletion of Rbpj in the hypothalamus does not affect expression of Hes1 within the posterior hypothalamus or expression of Hes5. In contrast, expression of activated Notch within the hypothalamus results in ectopic Hes5 expression and increased Hes1 expression, which is sufficient to disrupt pituitary development and postnatal expansion. Conclusions: Taken together, our results indicate that Rbpj-dependent Notch signaling within the developing hypothalamus is not necessary for pituitary development, but persistent Notch signaling and ectopic Hes5 expression in hypothalamic progenitors affects pituitary induction and expansion. Developmental Dynamics 244:921–934, 2015. © 2015 Wiley Periodicals, Inc.
14 citations
Cites background from "Fibroblast growth factors, their re..."
...Immunohistochemistry reveals uniform expression of phosophorylated-ERK1/ 2 (pERK) within RP, indicating activation of FGF signaling within the control pituitary (Powers et al., 2000; Corson et al., 2003) D E V E L O P M E N T A L D Y N A M IC S...
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...Immunohistochemistry reveals uniform expression of phosophorylated-ERK1/ 2 (pERK) within RP, indicating activation of FGF signaling within the control pituitary (Powers et al., 2000; Corson et al., 2003) D E V E L O P M E N T A L D Y N A M IC S Fig....
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TL;DR: The findings indicate that the antitumor effects of COX‐2 inhibition in EADC cells may be mediated via suppression of FGF‐2, and that COx‐2 may be a clinically relevant molecular marker in the management of human EadC.
Abstract: Inhibition of cyclooxygenase (COX)-2 is reported to suppress growth and induce apoptosis in human esophageal adenocarcinoma (EADC) cells, although the precise biologic mechanism is unclear. In this study we tested the hypothesis that the antitumor activity of COX-2 inhibitors may involve modulation of basic fibroblast growth factor (FGF-2), which is overexpressed in EADC. We evaluated the effects of NS-398, a selective COX-2 inhibitor, on FGF-2 expression and proliferation of EADC cell lines that express COX-2 and those that do not. We also correlated COX-2 and FGF-2 expression with clinico-pathologic findings and outcome in a well-characterized series of surgically resected EADC tissues. Seg-1 cells robustly expressed COX-2 and FGF-2, whereas Bic-1 cells expressed neither transcript. FGF-2 was reduced to undetectable levels in Seg-1 cells following NS-398 treatment, but increased within 4 h of drug removal. NS-398 significantly inhibited the growth of Seg-1 cells, and this effect was ameliorated by addition of exogenous FGF-2. In contrast, NS-398 had no effect on Bic-1 cell proliferation and FGF-2 alone had no effect on proliferation of either cell line. NS-398, or a neutralizing anti-FGF-2 antibody, induced apoptosis in Seg-1 cells, and these effects were inhibited by addition of exogenous FGF-2. COX-2 protein was strongly expressed in 46% (10/22) of EADCs, and was associated with a trend towards reduced disease-free survival. These findings indicate that the antitumor effects of COX-2 inhibition in EADC cells may be mediated via suppression of FGF-2, and that COX-2 may be a clinically relevant molecular marker in the management of human EADC.
14 citations
Cites background from "Fibroblast growth factors, their re..."
...Basic fibroblast growth factor (FGF-2) is the prototypic member of a family of related genes encoding heparin-binding proteins with growth-, anti-apoptotic- and angiogenic activity [6]....
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TL;DR: The results suggest that early phosphorylation of JNK is a specific mechanism involved in microtubule depolymerization by certain MBAs, and this work indicates that activation of J NK is principally required for XRP44X- and CA4-induced microtubules depolymersization and G2/M phase arrest.
Abstract: Microtubule-binding agents (MBAs) form one of the most important anticancer-drug families, but their molecular mechanisms are poorly understood. MBAs such as paclitaxel (PTX) stabilize microtubules, whereas XRP44X (a novel pyrazole) and combretastatins A4 (CA4) destabilize microtubules. These two different types of MBAs have potent antitumor activity. Comparisons of their effects on signal transduction and cellular responses will help uncover the molecular mechanism by which MBAs affect tumor cells. We used MCF-7 cells to compare the effects of the three MBAs on the cytoskeleton, cell cycle distribution, and activation of the three major mitogen-activated protein kinase (MAPK) signaling cascades [extracellular signal-related kinases, c-Jun N-terminal kinase (JNK), and p38 MAPK] using pharmacological inhibitors. The G2/M phase arrest was induced following polymerization of microtubules by PTX and depolymerization by XRP44X and CA4. The three major MAPKs were rapidly activated by XRP44X, and extracellular signal-related kinases and p38 by PTX, whereas JNK did not quickly respond to PTX. Pharmacological inhibitors indicated that activation of JNK is principally required for XRP44X- and CA4-induced microtubule depolymerization and G2/M phase arrest. Our results suggest that early phosphorylation of JNK is a specific mechanism involved in microtubule depolymerization by certain MBAs.
14 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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