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At least 109 records · Page 6Linked to original sources
PubMed2003

Induction of stromelysin-1 (MMP-3) by fibroblast growth factor-2 (FGF-2) in FGF-2-/- microvascular endothelial cells requires prolonged activation of extracellular signal-regulated kinases-1 and -2 (ERK-1/2).

Basic fibroblast growth factor (FGF-2) and matrix metalloproteinases (MMPs) play key roles in vascular remodeling. Because FGF-2 controls a number of proteolytic activities in various cell types, we tested its effect on vascular endothelial cell expression of MMP-3 (stromelysin-1), a broad-spectrum proteinase implicated in coronary atherosclerosis. Endothelial cells (EC) from FGF-2-/- mice are highly responsive to exogenous FGF-2 and were therefore used for this study. The results showed that treatment of microvascular EC with human recombinant FGF-2 results in strong induction of MMP-3 mRNA and protein expression. Upregulation of MMP-3 mRNA by FGF-2 requires de novo protein synthesis and activation of the ERK-1/2 pathway. FGF-2 concentrations (5-10 ng/ml) that induce rapid and prolonged (24 h) activation of ERK-1/2 upregulate MMP-3 expression. In contrast, lower concentrations (1-2 ng/ml) that induce robust but transient (<8 h) ERK-1/2 activation are ineffective. Inhibition of ERK-1/2 activation at different times (-0.5 h to +8 h) of EC treatment with effective FGF-2 concentrations blocks MMP-3 upregulation. Thus, FGF-2 induces EC expression of MMP-3 with a threshold dose effect that requires sustained activation of the ERK-1/2 pathway. Because FGF-2 controls other EC functions with a linear dose effect, these features indicate a unique role of MMP-3 in vascular remodeling.

Animals↗
PubMed1998

Prolactin induces expression of FGF-2 and a novel FGF-responsive NonO/p54nrb-related mRNA in rat lymphoma cells.

The rat Nb2-11C lymphoma cell line expresses high affinity prolactin (PRL) receptors, and requires lactogenic hormones for survival and proliferation. We have applied differential display to identify genes which are differentially induced in Nb2-11C cells following PRL stimulation, or which are constitutively expressed in the PRL-independent Nb2-Sp cells. In the present study we characterized a clone (22c.2) which was expressed in Nb2-Sp cells, and in Nb2-11C cells given PRL for 3 h but not in untreated cells. The 279 bp cDNA had 95% homology with the 3' end of the murine 2.6 kb FGF-inducible gene 14 (FIN14). When clone 22c.2 was used to screen a Nb2-Sp cDNA library to obtain a longer cDNA, a unique 1039 bp clone PNR (Prolactin-responsive/ NonO-Related) was isolated, subcloned and sequenced. The deduced amino acid sequence encoded by the PNR open reading frame had significant homology with a family of RNA- and DNA-binding proteins which include the human polypyrimidine tract-binding protein (PTB)-associated splicing factor (PSF), the murine non-POU-domain-containing octamer-binding protein (NonO) and the human NonO homologue p54nrb. Nb2-11C cells expressed three PNR-related mRNA transcripts of 2.5, 3.0 and > 10 kb. Expression of the 2.5 and 3.0 kb transcripts were increased at least 4-fold within 3 h of PRL treatment. PNR expression was also significantly stimulated within 3 h by addition of FGF-2 to either Nb2-11C or Nb2-Sp cells, although alone FGF-2 was not mitogenic for either cell line. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed the expression of both FGF-2 and FGF receptor mRNA in Nb2 cells. raising the possibility of an autocrine or paracrine function for FGF-2 in lymphoma cells. Furthermore, PRL rapidly stimulated the expression of FGF-2 mRNA in a time- and dose-dependent manner in both Nb2-11C and Nb2-Sp cells. FGF-2 expression was increased within 1 h and was maintained at a high level for at least 10 h following treatment with 2 ng/ml PRL. Western blotting with anti-FGF2 antisera demonstrated PRL stimulation of intracellular accumulation, but not secretion of immunoreactive FGF-2. The observation of PRL-responsive expression of FGF-2 in Nb2 cells suggests a previously unrecognized pathway for PRL action in lymphoid cells.

Amino Acid Sequence↗
PubMed1997

Murine FGF-12 and FGF-13: expression in embryonic nervous system, connective tissue and heart.

The molecular cloning of cDNAs encoding murine fibroblast growth factor-13 (FGF-13/FHF-2) and three isoforms of murine FGF-12 (FHF-1) is described. Like their highly conserved human counterparts, murine FGF-12 and FGF-13 are part of a distinct subfamily of FGF-like proteins characterized by a greater degree of amino acid sequence cross-homology and by conserved N-terminal domains which do not include secretion signal sequences. In addition to their expression in several adult tissues, both of these FGF genes are prominently and regionally expressed in midgestation mouse embryos, as revealed by in situ hybridization. Fgf12 and fgf13. RNAs were detected in developing central nervous system in cells outside the proliferating ependymal layer, and fgf13 RNA was also found throughout the peripheral nervous system. Fgf12 is expressed in developing soft connective tissue of the limb skeleton and in presumptive connective tissue linking vertebrae and ribs. Both FGF genes are also expressed in the myocardium of the heart, with fgf12 RNA found only in the atrial chamber and fgf13 RNA detected in both atrium and ventricle. On the basis of their novel structure and patterns of expression, FGF-12 and FGF-13 are anticipated to perform embryonic functions distinct from other known FGF molecules.

Adult↗
PubMed1998

FGF-3 and FGF-4 elicit distinct oncogenic properties in mouse mammary myoepithelial cells.

Fibroblast Growth Factors 3 (FGF-3) and 4 (FGF-4) were compared for the effects they each exert on EF43 mouse cells. This non-transformed mammary cell line appears to be myoepithelial mainly because it expresses alpha-smooth muscle actin. The EF43 cells were infected with similar vectors that carry either the short fgf-3 sequence (the product of which goes into the secretory pathway), fgf-4 or the selection gene only as control. In syngeneic animals, EF43.fgf-3 cells were tumorigenic only when orthotopically implanted whereas EF43.fgf-4 cells invariably gave rise to aggressive tumors. However, both tumor types were metastatic as evidenced by the blue micrometastases observed when the implanted cells expressed lacZ. In vitro, the FGF-3 producing cells were strongly invasive in matrigel coated chambers whereas the EF43.fgf-4 cells only were invasive in type I-collagen gels. Interestingly, FGF-3 production greatly stimulated the synthesis of pro-MMP-9 (Matrix Metalloprotease-9) and, to a lesser extent, that of pro-MMP-2. FGF-3 also up-regulated the production of plasminogen activators. In contrast, FGF-4 had no effect on these secretions and the medium conditioned by the EF43.fgf-4 cells displayed the largest plasminogen activator-inhibitor activity. These results show that FGF-3 and FGF-4 have distinct mechanisms of action on myoepithelial cells.

Animals↗
PubMed1997

Overlapping expression and redundant activation of mesenchymal fibroblast growth factor (FGF) receptors by alternatively spliced FGF-8 ligands.

FGF-8 is a member of the family of fibroblast growth factors and is expressed during vertebrate embryo development. Eight potential FGF-8 isoforms are generated by alternative splicing in mice, several of which are expressed during embryogenesis in epithelial locations. The significance of the multiple isoforms is currently unknown. In this report, we investigate the expression patterns and the specificity of the FGF-8 isoforms for known fibroblast growth factor (FGF) receptors. RNAs for seven of the eight potential isoforms are present at multiple sites of embryonic Fgf8 expression. None of the FGF-8 isoforms exhibited activity when assayed with BaF3 cells expressing the "b" splice forms of FGF receptors 1-3, which are mostly expressed in epithelial tissues. Mesenchymally expressed "c" splice forms of FGF receptors 2 and 3 and FGF receptor 4 were activated by several FGF-8 isoforms. These findings are consistent with the hypothesis that the multiple FGF-8 isoforms are functionally redundant and function to signal in paracrine (epithelial to mesenchymal) contexts.

Alternative Splicing↗
PubMed1998

Differential regulation of potassium currents by FGF-1 and FGF-2 in embryonic Xenopus laevis myocytes.

1. Fibroblast growth factors (FGFs) are involved in the regulation of many aspects of muscle development. This study investigated their role in regulating voltage-dependent K+ currents in differentiating Xenopus laevis myocytes. Both FGF-1 and FGF-2 are expressed by developing muscle cells, so their actions were compared. Experiments were performed on cultured myocytes isolated from stage 15 embryos. 2. Long-term exposure of the embryonic myocytes to FGF-1 downregulated inward rectifier K+ current (IK(IR)) density as well as both sustained and inactivating voltage-dependent outward K+ currents (IK,S and IK,I, respectively) and their densities. In contrast, FGF-2 upregulated these currents, although, because of an increase in capacitance caused by FGF-2, current density did not change with this factor. 3. The regulation of IK(IR) by FGF-1 was prevented by the cytoplasmic tyrosine kinase inhibitor herbimycin A, but that of IK,S and IK,I was unaffected, indicating that FGF-1 achieves its regulatory effects on electrical development via separate signalling pathways. The receptor tyrosine kinase inhibitor genistein in isolation suppressed K+ currents, but this may have occurred through a channel-blocking mechanism. 4. In many cells, IK, S was found to be composed of two components with differing voltage dependencies of activation. The FGFs brought about an alteration in the amount of total IK,S by equal effects on each component. Conversely, herbimycin A increased the proportion of low voltage-activated current without affecting total current amplitude. Therefore, we suggest that a single species of channel whose voltage dependence is shifted by tyrosine phosphorylation generates IK,S. 5. In summary, FGF-1 and FGF-2 exert opposite effects on voltage-dependent K+ currents in embryonic myocytes and, furthermore, FGF-1 achieves its effects on different K+ currents via separate second messenger pathways.

Animals↗
PubMed1995

Immunohistochemical localization of fibroblast growth factor-1 (FGF-1) and FGF-2 in cultured human ameloblastoma epithelial cells and ameloblastoma tissues.

Fibroblast growth factor-1 (FGF-1) and FGF-2 are mitogenic polypeptides that may contribute to neoplastic cell proliferation. In the present study, we established a serum-free culture system for ameloblastoma cells and demonstrated that the addition of FGF-1 and FGF-2 enhanced cell growth in a dose-dependent manner. Immunoperoxidase staining of cultured cells demonstrated strong expression of FGF-1 and FGF-2. In tissue specimens, FGF-1 was localized in epithelial cell components of ameloblastomas, whereas FGF-2 was mainly found in the basement membranes with only moderate staining in epithelium. These data suggest that both FGF-1 and FGF-2 may contribute to the growth and development of ameloblastomas.

Adolescent↗
PubMed2001

Differential regulation of the fibroblast growth factor (FGF) family by alpha(2)-macroglobulin: evidence for selective modulation of FGF-2-induced angiogenesis.

The fibroblast growth factor (FGF) family has an important role in processes such as angiogenesis, wound healing, and development in which precise control of proteinase activity is important. The human plasma proteinase inhibitor alpha(2)-macroglobulin (alpha(2)M) regulates cellular growth by binding and modulating the activity of many cytokines and growth factors. These studies investigate the ability of native and activated alpha(2)M (alpha(2)M*) to bind to members of the FGF family. Both alpha(2)M and alpha(2)M* bind specifically and saturably to FGF-1, -2, -4, and -6, although the binding to alpha(2)M* is of significantly higher affinity. Neither alpha(2)M nor alpha(2)M* bind to FGF-5, -7, -9, or -10. FGF-2 was chosen for more extensive study in view of its important role in angiogenesis. It was demonstrated that FGF-2 binds to the previously identified TGF-beta binding site. The alpha(2)M* inhibits FGF-2-dependent fetal bovine heart endothelial cell proliferation in a dose-dependent manner. Unexpectedly, alpha(2)M* does not affect FGF-2-induced vascular tubule formation on Matrigel basement membrane matrix or collagen gels. Further studies demonstrate that FGF-2 partitions between fluid-phase alpha(2)M* and solid-phase Matrigel or collagen. These studies suggest that the ability of alpha(2)M* to modulate the activity of FGF-2 is dependent on an interplay with extracellular matrix components. (Blood. 2001;97:3450-3457)

Animals↗
PubMed1993

Expression of messenger ribonucleic acids encoding for basic fibroblast growth factor (FGF) and alternatively spliced FGF receptor in human fetal ovary and uterus.

Basic fibroblast growth factor (bFGF) is an angiogenic and mitogenic peptide that may have modulatory effects in the adult ovary and uterus. The FGF receptor is a tyrosine kinase and has similar affinity for both acidic FGF and bFGF. The ligand-binding portion of the receptor has three immunoglobulin-like domains. bFGF and the FGF receptor have been localized in the fetal rat ovary and Mullerian duct. bFGF is a proliferative agent recently shown to be vital for long term cultures of mouse fetal primordial germ cells. Expression of bFGF and FGF receptor mRNA have not heretofore been reported in human fetal ovary and uterus. We prepared RNA from whole human fetal ovaries and uteri at 10, 15, 19, and 22 weeks gestation. After reverse transcription of the RNA into cDNA, we used polymerase chain reaction (PCR) primers directed to specific portions of bFGF and the FGF receptor and performed PCR amplification using the fetal cDNA. We found mRNA expression of bFGF and two forms of FGF receptor in all fetal ovaries and uteri at these developmental stages. One of the PCR products for the FGF receptor was the sequence that contained three immunoglobulin-like domains, whereas a second PCR-amplified fragment was consistent with a FGF receptor mRNA that has a 267-basepair deletion in the first immunoglobulin-like loop. We conclude that bFGF and two forms of the FGF receptor mRNA are expressed in human fetal ovary and uterus. The finding that both bFGF and the FGF receptor are concurrently expressed suggests that bFGF may serve as an autocrine or paracrine modulator during early development of the human reproductive tract.

Base Sequence↗
PubMed2001

BMP-2 augments FGF-induced differentiation of PC12 cells through upregulation of FGF receptor-1 expression.

When exposed to various neurotrophic factors, including fibroblast growth factors (FGF)-1 and -2, rat pheochromocytoma-derived PC12 cells differentiate into sympathetic neuron-like cells possessing elongated neurites. We found that while bone morphogenetic protein-2 (BMP-2) exerted little effect by itself on the differentiation of PC12 cells, in combination with FGF it strongly induced neurite outgrowth, even at subthreshold concentrations of FGF. Analysis of gene expression revealed that FGF receptor-1 (FGFR-1) mRNA was abundantly expressed in PC12 cells and that its expression was upregulated by pretreating the cells with BMP-2. Crosslinking the receptors with (125)I-FGF-2 and then immunoprecipitating them confirmed that expression of FGFR-1, but not other FGF receptor types, was enhanced by BMP-2. Furthermore, Scatchard analyses revealed that the numbers of FGF-2 binding sites were increased by approximately 40% after BMP-2 treatment. Pretreatment with BMP-2 also enhanced peak and sustained levels of FGF-induced ERK1/2 phosphorylation in PC12 cells. Finally, the augmentation of neurotrophic activity by BMP-2 was inhibited by SU5402, an FGFR-1 inhibitor. These findings indicate that BMP-2 augments FGF-induced differentiation of PC12 cells through selective upregulation of FGFR-1 expression, and suggest that BMP-2 and FGF act in concert to regulate cell differentiation in the nervous system.

Animals↗
PubMedDate not supplied

[The effect of fibroblast growth factors (FGF-2, FGF-4) on the development of parthenogenetic mouse embryos].

We studied the effects of two growth factors, FGF-2 and FGF-4, on development of diploid parthenogenetic mouse embryos (CBA x C57BL/6)F1. Parthenogenetic embryos were treated with FGF-2 or FGF-4 in vitro at the morula stage and, after they reached the blastocyst stage, transplanted into the uteri of pseudopregnant females. FGF-2 and FGF-4 did not affect the number of blastocysts formed in vitro or implantation into the uterus. However, FGF-2 and FGF-4 at optimal doses decreased the mortality rate of parthenogenetic embryos at the early postimplantation stages and increased twofold the number of embryos that developed in utero to the somite stages: 42 and 36%, respectively, versus 20% in the control. The results obtained suggest that the treatment of parthenogenetic mouse embryos with FGF-2 or FGF-4 modulate the effects of genomic imprinting and prolong the development of parthenogenetic embryos at the postimplantation stages.

Animals↗
PubMed1997

FGF-1 and FGF-7 induce distinct patterns of growth and differentiation in embryonic lung epithelium.

Fibroblast growth factors (FGFs) and receptors (FGFRs) are expressed in the developing lung and appear to be major regulators of lung growth and differentiation. By using mesenchyme-free lung epithelial cultures we show that FGF-1 (aFGF) and FGF-7 (KGF) produce different effects in the developing lung. FGF-1 stimulates epithelial proliferation that results in bud formation (branching), while FGF-7 promotes epithelial proliferation that leads to formation of cyst-like structures. In addition, FGF-7 stimulates epithelial differentiation, stimulating expression of SP-A and SP-B mRNA throughout the explant, and inducing formation of focal areas of highly differentiated cells. The FGF-1 effects on differentiation are limited to induction of surfactant protein SP-B mRNA at the tips of the explant. The FGF-induced patterns of growth appear to correlate with the distribution of epithelial FGFRs mRNAs; FGFR-2 IIIb (KGFR) is diffusely expressed in the day 11 lung epithelium, while FGFR-4 appears in distal but not in proximal sites. We propose that cyst-like structures may result from FGF-7 binding to the uniformly distributed FGFR-2-IIIb. Lung bud formation may be regulated by FGF-1 and/or other ligands binding to FGFR-2 and a distally located FGFR, such as FGFR-4, leading to an increasing binding and activation of FGFRs at the tips of the explant. Thus, in the embryonic lung epithelium, growth effects of FGFs appear to be dependent on location of FGFRs, while effects on differentiation are ligand-dependent.

Animals↗
PubMed1999

Localization and regulation of basic fibroblast growth factor (FGF-2) and FGF receptor-1 in rat superior cervical ganglion after axotomy.

In response to peripheral nerve lesion, synthesis of basic fibroblast growth factor (FGF-2) increases in sensory ganglia and motoneurons. Here, we investigated the axotomy-induced regulation of FGF-2 and FGF receptor-1 (FGFR-1) expression in the autonomic nervous system using the sympathetic superior cervical ganglion of the adult rat as a model. Transcripts for both proteins were detected by ribonuclease protection assay. Western blotting indicated the presence of all three FGF-2 isoforms (18, 21, and 23 kD) in the superior cervical ganglion. Immunohistochemical analysis revealed FGF-2 localization in nuclei of satellite cells surrounding postganglionic perikarya. After transection of the carotid nerves, the number of FGF-2-immunoreactive glial cells increased. FGF-2 mRNA was up-regulated within 6 h and remained elevated for 3 weeks. The 18-, 21-, and 23-kD isoforms were all increased 7 days after axotomy. FGFR-1 immunoreactivity was observed in neuronal and nonneuronal nuclei in the normal rat superior cervical ganglion. In contrast to FGF-2, expression of FGFR-1 was unchanged in ganglia after axotomy. Taken together, the present results suggest that FGF-2 participates in neuron-glial interactions of sympathetic ganglia and may be involved in sympathetic neuron survival or nerve regeneration after nerve lesion.

Animals↗
PubMed2005

Chronic obstructive pulmonary disease is associated with enhanced bronchial expression of FGF-1, FGF-2, and FGFR-1.

An important feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, the molecular mechanisms of which are poorly understood. In this study, the role of fibroblast growth factors (FGF-1 and FGF-2) and their receptor, FGFR-1, was assessed in bronchial airway wall remodelling in patients with COPD (FEV1 < 75%; n = 15) and without COPD (FEV1 > 85%; n = 16). FGF-1 and FGFR-1 were immunolocalized in bronchial epithelium, airway smooth muscle (ASM), submucosal glandular epithelium, and vascular smooth muscle. Quantitative digital image analysis revealed increased cytoplasmic expression of FGF-2 in bronchial epithelium (0.35 +/- 0.03 vs 0.20 +/- 0.04, p < 0.008) and nuclear localization in ASM (p < 0.0001) in COPD patients compared with controls. Elevated levels of FGFR-1 in ASM (p < 0.005) and of FGF-1 (p < 0.04) and FGFR-1 (p < 0.001) in bronchial epithelium were observed. In cultured human ASM cells, FGF-1 and/or FGF-2 (10 ng/ml) induced cellular proliferation, as shown by [3H]thymidine incorporation and by cell number counts. Steady-state mRNA levels of FGFR-1 were elevated in human ASM cells treated with either FGF-1 or FGF-2. The increased bronchial expression of fibroblast growth factors and their receptor in patients with COPD, and the mitogenic response of human ASM cells to FGFs in vitro suggest a potential role for the FGF/FGFR-1 system in the remodelling of bronchial airways in COPD.

Aged↗
PubMed2004

Relative retention of the fibroblast growth factors FGF-1 and FGF-2 on strong cation-exchange sorbents.

The isocratic retention of two heparin-binding fibroblast growth factors, FGF-1 (acidic FGF) and FGF-2 (basic FGF), was compared on a set of six preparative strong cation-exchange adsorbents. The FGFs comprise a solute pair that are structurally equivalent, yet differ in protein parameters of potential importance in cation-exchange chromatography, such as isoelectric point, net charge, and the number and distribution of basic amino acids. The cation-exchange adsorbents comprise a diverse set of materials in common use for protein purification, with physical and chemical properties that have been characterized and described previously. Isocratic k' values for the two proteins obtained on each adsorbent at several different [NaCl] are compared with one another and with corresponding data for hen egg lysozyme, which is also strongly retained on cation-exchangers. Of the six adsorbents examined, three showed strong retention of both FGFs, with equivalent k' values for FGF-1 and FGF-2. Three others, which showed weaker overall retention for the FGF pair, showed much larger retention differences between FGF-1 and FGF-2. The trends in retention order among the stationary phases are very similar to those seen previously with other unrelated proteins. However, retention differences between the two FGFs, and between the FGFs and lysozyme, do not correlate well with simple charge properties such as net charge, indicating, as in some previous studies, the importance of local regions on the protein surface in determining retention. These observations are interpreted in terms of the structural features of the proteins and the physicochemical properties of the adsorbents.

Adsorption↗
PubMed2004

Coexpression and regulation of the FGF-2 and FGF antisense genes in leukemic cells.

Fibroblast growth factor-2 (FGF-2) is a growth and survival factor whose expression is elevated in many hematopoietic malignancies. A natural antisense RNA (FGF-AS) has been implicated in the posttranscriptional regulation of FGF-2 mRNA expression. We demonstrate for the first time that FGF sense and antisense RNAs are coordinately expressed and translated in hematopoietic cells and tissues. Cytokine stimulation of growth-arrested K562 cells elicited a rapid transient increase in FGF-AS mRNA expression followed by a slower but sustained increase in FGF-2 mRNA. This was accompanied by a marked increase in the expression and nuclear translocation of FGF-2 and the FGF-AS encoded protein, GFG/NUDT6. These findings suggest a role for both FGF-2 and GFG proteins in the cell survival and proliferation of lymphoid and myeloid tumor cells.

Alternative Splicing↗
PubMed2003

Differential tyrosine phosphorylation of fibroblast growth factor (FGF) receptor-1 and receptor proximal signal transduction in response to FGF-2 and heparin.

The sulfated regions in heparan sulfate and heparin are known to affect fibroblast growth factor (FGF) function. We have studied the mechanism whereby heparin directs FGF-2-induced FGF receptor-1 (FGFR-1) signal transduction. FGF-2 alone stimulated maximal phosphorylation of Src homology domain 2 tyrosine phosphatase (SHP-2) and the adaptor molecule Crk, in heparan sulfate-deficient Chinese hamster ovary (CHO) 677 cells expressing FGFR-1. In contrast, for phospholipase Cgamma(1) (PLCgamma(1)) and the adaptor molecule Shb to be maximally tyrosine-phosphorylated, cells had to be stimulated with both FGF-2 and heparin (100 ng/ml). Tyrosine residues 463 in the juxtamembrane domain and 766 in the C-terminal tail in FGFR-1 are known to bind Crk and PLCgamma(1), respectively. Analysis of tryptic phosphopeptide maps of FGFR-1 from cells stimulated with FGF-2 alone and FGF-2 together with heparin showed that FGF-2 alone stimulated a several-fold increase in tyrosine 463 in the juxtamembrane domain. In contrast, heparin had to be included in order for tyrosine 766 to be phosphorylated to the same fold level. Our data imply that tyrosine 463 is phosphorylated and able to transduce signals in response to FGF-2 treatment alone; furthermore, we suggest that FGFR-1 dimerization/kinase activation is stabilized by heparin.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Administration of a liposomal FGF-2 peptide vaccine leads to abrogation of FGF-2-mediated angiogenesis and tumor development.

Basic fibroblast growth factor (FGF-2) is an important stimulator of angiogenesis that has been implicated in neoplastic progression. Attempts to neutralize or modulate FGF-2 have met with some success in controlling neovascularity and tumor growth. In the present study, two peptides: one corresponding to the heparin binding domain and the other to the receptor binding domain of FGF-2, exerted dose-dependent inhibition of FGF-2-stimulated human umbilical vein endothelial cell proliferation (IC(50)=70 and 20 microg/ml, respectively). The identification of these functional regions suggested that targeting these domains might be an approach for the modulation of FGF-2 function. To investigate this possibility, we vaccinated mice with either the heparin binding domain peptide or the receptor binding domain peptide of FGF-2 in a liposome/adjuvant format, and analyzed the effect of vaccination on FGF-2-driven angiogenesis, tumor development and immune status. Mice vaccinated with the heparin binding domain peptide generated a specific antibody response to FGF-2, blocked neovascularization in a gelfoam sponge model of angiogenesis, and inhibited experimental metastasis by >90% in two tumor models: the B16BL6 melanoma and the Lewis lung carcinoma. These effects were not observed in mice treated with the receptor binding domain peptide conjugated to liposomes or liposomes lacking conjugated peptide. These data suggest that a heparin binding domain peptide of FGF-2, when presented to a host in a liposomal adjuvant formulation, can ultimately lead to inhibition of angiogenesis and tumor growth.

Amino Acid Sequence↗