Angiogenesis: health and disease.
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Angiogenesis Inducing Agents↗
Biomedical subjects
A Bikfalvi
Publications and source records attributed to A Bikfalvi.
Long-term inhibition of glioma growth by systemic administration of human PEX.
AIM: The growth of gliomas depends on the balance of factors stimulating or inhibiting angiogenesis, tumor cell invasion and proliferation. The administration of endogenous inhibitors to experimental human gliomas in animal models resulted in a significant inhibition of tumor growth. It is becoming apparent that resistance can develop over time to many types of endogenous inhibitors and seems to be influenced by the tumor type and system of delivery. METHODS: We recently isolated a potent endogenous inhibitor, called human PEX, from human glioma cells in culture. Human PEX is a potent inhibitor of angiogenesis, tumor and endothelial cell proliferation and migration. In this paper, we investigated the ability of human PEX to sustain inhibition of glioma growth for a prolonged period of time. We initially developed a recombinant form of the inhibitor and showed that this form had similar in vitro and in vivo activities to the natural one. Human PEX was then administered to nude mice intracranial human glioma model, in combination with metronomic chemotherapy, for a period of 185 days, starting 15 days after tumor cells implantation. RESULTS: Our data showed that the systemic administration of human PEX mantained a very prolonged inhibition of glioma growth (50% survival of animals treated with 2 mg/kg/days was 160 days vs 24 days of the control) and had a synergistic effect with low dose chemotherapy. Histological analysis of tumors, showed that treatment with PEX was associated with a decrease of vascularity, cell proliferation, and increase in apoptosis. CONCLUSION: These data indicate that human PEX controls tumor growth by separate mechanisms. In addition, treatment with PEX produced well delineated tumors, indicating the persistence of a direct anti-invasive effect of the molecule even after a prolonged period of treatment.
Angiogenesis Inhibitors↗
Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2.
Angiogenesis, tumor cell proliferation, and migration are the hallmarks of solid tumors, such as gliomas. This study demonstrates that a fragment derived from the autocatalytic digestion of matrix metalloproteinase (MMP)-2, called PEX, acts simultaneously as an inhibitor of glioma angiogenesis, cell proliferation, and migration. PEX is detected in the cultured medium of various human glioma, endothelial, breast, and prostate carcinoma cell lines. PEX is purified from the medium of glioma cell lines by chromatography, where PEX is constitutively expressed as a free and a TIMP-2-bound form. In human glioma tissue, PEX expression correlates with histological subtype and grade and with alpha v beta 3 integrin expression to which it is bound. Systemic administration of PEX to s.c. and intracranial human glioma xenografts results in a 99% suppression of tumor growth with no signs of toxicity. Thus, PEX is a very promising candidate for the treatment of human malignant gliomas.
Adult↗
Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo.
This study evaluates the efficacy of the combination of an antiangiogenic drug and conventional chemotherapeutics for the treatment of experimental human gliomas. As an antiangiogenic, we used recombinant human PEX, a fragment of matrix metalloproteinase-2 that we have previously shown to have a significant antimitotic, anti-invasive, and antiangiogenic properties against human glioblastoma in vitro and in vivo. We used carboplatin and etoposide as the two chemotherapeutic drugs routinely used in our institution (Ospedale Maggiore de Milano) for the treatment of malignant gliomas. Conventional chemotherapeutic drugs were administered at high dose or at a low and semicontinuous regimen. Combined treatment of high-dose chemotherapy and PEX did not produce an improvement of survival in comparison with chemotherapy alone, but it was associated with a decrease in tumor volume, vascularity, and proliferative index and an increased apoptosis. All of these animals experienced severe side effects. The longest survival was documented in animals submitted to low and semicontinuous chemotherapy and antiangiogenic treatment. This regimen was associated with no side effects, marked decrease in tumor volume, vascularity, and proliferative index, and an increased apoptosis. Our data suggest that low-dose chemotherapy in combination with PEX can be successfully used against human malignant glioma in vivo.
Angiogenesis Inhibitors↗
Solution structure and interaction with basic and acidic fibroblast growth factor of a 3-kDa human platelet factor-4 fragment with antiangiogenic activity.
Platelet factor-4 is a protein belonging to the family of ELR-negative CXC chemokines which binds to fibroblast growth factor and inhibits its mitogenic activity. Platelet factor-4 also inhibits tumor growth by mechanisms involving antiangiogenesis. Antiangiogenic activity in vitro has also been shown for the 24-residue C-terminal fragment of the protein, which decreases the affinity between basic fibroblast growth factor and its cell-surface receptor. In this study, the preferential conformation of this fragment in solution has been determined and has been found to be composed of two helical subdomains. In addition, we show that the fragment forms a specific 1:1 complex with acidic and basic fibroblast growth factors and that both subdomains are probably required for inhibition of fibroblast growth factor-driven mitogenesis. Finally, we show that the binding of the fragment alters the structure of the fibroblast growth factors, although some of such alterations do not seem related with the inhibition of mitogenic activity. Since this fragment has recently been shown to inhibit fibroblast growth factor-induced angiogenesis in vivo when injected intraperitoneally, these results are relevant for developing new antiangiogenic treatments.
Amino Acid Sequence↗
Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and -independent mechanisms.
We undertook a series of systematic studies to address the role of fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) activity in tumor growth and angiogenesis. We expressed dominant-negative FGFR2 (FGFR2-DN) or FGFR1 (FGFR1-DN) in glioma C6 cells by using constitutive or tetracycline-regulated expression systems. Anchorage-dependent or independent growth was inhibited in FGFR-DN-expressing cells. Tumor development after xenografting FGFR-DN-expressing cells in immunodeficient mice or after transplantation in rat brain was strongly inhibited. Quantification of microvessels demonstrated a significant decrease in vessel density in tumors derived from FGFR-DN-expressing cells. Furthermore, in a rabbit corneal assay, the angiogenic response after implantation of FGFR-DN-expressing cells was decreased. In tumors expressing FGFR-DN, vascular endothelial growth factor expression was strongly inhibited as compared with control tumor. These results indicate that inhibition of FGF activity may constitute a dominant therapeutic strategy in the treatment of FGF-producing cerebral malignancies and may disrupt both angiogenesis-dependent and -independent signals required for glioma growth and invasion.
Animals↗
A short peptide domain of platelet factor 4 blocks angiogenic key events induced by FGF-2.
Platelet factor 4 (PF-4) is a CXC-chemokine with strong anti-angiogenic properties. We have shown previously that PF-4 inhibits angiogenesis by associating directly with fibroblast growth factor 2 (FGF-2), inhibiting its dimerization, and blocking FGF-2 binding to endothelial cells. We now have characterized a small peptide domain (PF-447-70) derived from the C-terminus of PF-4, which conserves anti-angiogenic effects of the parent protein. PF-447-70 inhibited internalization of 125I-FGF-2 by endothelial cells in a time-dependent manner. The peptide reduced FGF-2-stimulated cell migration to control levels in wounded monolayers of bovine capillary endothelial cells. PF-447-70 also reduced FGF-2 induced phosphorylation of MAP kinases ERK-1 and ERK-2, which are essential for migration and survival of endothelial cells. In a serum-free ex vivo angiogenesis assay, the peptide blocked microvessel outgrowth by 89%. A single amino acid substitution within PF-447-70 abolished all inhibitory activities. To simulate a real anti-angiogenic treatment situation, we administered PF-447-70 systemically to mice implanted subcutaneously with FGF-2 containing gelatin sponges with the result of sparse, scattered, and immature vessel growth. The small peptide fragment derived from the angio-inhibitory CXC-chemokine PF-4 might be used as a starting point to develop anti-angiogenic designer drugs for angiogenesis-dependent pathologies such as cancer, diabetic retinopathy, and rheumatoid arthritis.
Amino Acid Sequence↗
Neural and angiogenic defects in eyes of transgenic mice expressing a dominant-negative FGF receptor in the pigmented cells.
Fibroblast growth factors (FGF) are multipotent cytokines with demonstrated mitogenic, neurotrophic and angiogenic properties. There is evidence that they have multiple functions during and after development of the vertebrate eye. Amongst these, the role of FGF receptor mediated signaling in the retinal pigmented epithelium (RPE) is not yet well understood. FGF-2 is produced in RPE cells and may play a role in photoreceptor development and/or survival in vivo. It may also stimulate growth of melanocytes and angiogenesis in the choroid. To address these questions, we have specifically disrupted FGF signaling by generating lines of transgenic mice expressing dominant-negative FGF receptor 1 (FGFR-1) in the pigmented cells. Histological analysis of the eyes were conducted on hemizygous and homozygous mice at different ages. In homozygotes, eye growth is strongly impaired during embryogenesis leading to massive eye degeneration seen in the early post-natal stages. In hemizygotes, the choroid is thinned and the finger-like junctions between RPE cells and photoreceptors are disrupted. Scanning electron microscopy of the choroid vasculature showed that choriocapillary density, diameter and branching are strongly affected. As mice age, they develop progressive retinal degeneration as evidenced by photoreceptor cell loss. Our results are in agreement with the hypothesis that FGF signaling in the RPE participates in photoreceptor survival in vivo. Our model provides evidence that FGF signaling is also involved in choroidal angiogenesis by a process that could relate to induction of terminal branching.
Animals↗
Target molecules for anti-angiogenic therapy: from basic research to clinical trials.
There is growing evidence that anti-angiogenic drugs will improve future therapies of diseases like cancer, rheumatoid arthritis and ocular neovascularisation. However, it is still uncertain which kind of substance, out of the large number of angiogenesis inhibitors, will prove to be a suitable agent to treat these human diseases. There are currently more than 30 angiogenesis inhibitors in clinical trials and a multitude of promising new candidates are under investigation in vitro and in animal models. Important therapeutic strategies are: suppression of activity of the major angiogenic regulators like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF); inhibition of function of alphav-integrins and matrix metalloproteinases (MMPs); the exploitation of endogenous anti-angiogenic molecules like angiostatin, endostatin or thrombospondin. Given the wide spectrum of diseases which could be treated by anti-angiogenic compounds, it is important for today's clinicians to understand their essential mode of action at a cellular and molecular level. Here we give an in-depth overview of the basic pathophysiological mechanisms underlying the different anti-angiogenic approaches used to date based on the most recent fundamental and clinical research data. The angiogenesis inhibitors in clinical trials are presented and promising future drug candidates are discussed.
Angiogenesis Inhibitors↗
Inhibition of in vitro angiogenesis by platelet factor-4-derived peptides and mechanism of action.
In this study, we examined in detail the interaction of platelet factor-4 (PF-4) with fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) and the effect of PF-4-derived synthetic peptides. We show that a peptide between amino acids 47 and 70 that contains the heparin-binding lysine-rich site inhibits FGF-2 or VEGF function. This is based on the following observations: PF-4 peptide 47-70 inhibited FGF-2 or VEGF binding to endothelial cells; it inhibited FGF-2 or VEGF binding to FGFRs or VEGFRs in heparan sulfate-deficient CHO cells transfected with FGFR1 (CHOFGFR1) or VEGFR2 (CHOmVEGFR2) cDNA; it blocked proliferation or tube formation in three-dimensional angiogenesis assays; and, finally, it competed with the direct association of (125)I-PF-4 with FGF-2 or VEGF, respectively, and inhibited heparin-induced FGF-2 dimerization. A shorter C-terminal peptide (peptide 58-70), which still contained the heparin-binding lysin-rich site, had no effect. Peptide 17-58, which is located in the central part of the molecule, although it does not inhibit FGF-2 or VEGF binding or biologic activity in endothelial cells, inhibited heparin-dependent binding of (125)I-FGF-2 or (125)I-VEGF to CHOmFGFR1 or CHOmVEGFR2 cells, respectively. Shorter peptides (peptides 34-58 and 47-58) did not show any of these effects.
Animals↗
Fibroblast growth factor receptors participate in the control of mitogen-activated protein kinase activity during nerve growth factor-induced neuronal differentiation of PC12 cells.
The current paradigm for the role of nerve growth factor (NGF) or FGF-2 in the differentiation of neuronal cells implies their binding to specific receptors and activation of kinase cascades leading to the expression of differentiation specific genes. We examined herein the hypothesis that FGF receptors (FGFRs) are involved in NGF-induced neuritogenesis of pheochromocytoma-derived PC12 cells. We demonstrate that in PC12 cells, FGFR expression and activity are modulated upon NGF treatment and that a dominant negative FGFR-2 reduces NGF-induced neuritogenesis. Moreover, FGF-2 expression is modulated by NGF, and FGF-2 is detected at the cell surface. Oligonucleotides that specifically inhibit FGF-2 binding to its receptors are able to significantly reduce NGF-induced neurite outgrowth. Finally, the duration of mitogen-activated protein kinase (MAPK) activity upon FGF or NGF stimulation is shortened in FGFR-2 dominant negative cells through inactivation of signaling from the receptor to the Ras/MAPK pathway. In conclusion, these results demonstrate that FGFR activation is involved in neuritogenesis induced by NGF where it contributes to a sustained MAPK activity in response to NGF.
Animals↗
[Role of fibroblast growth factor-2 in tumor angiogenesis].
Angiogenesis reflects a balance between stimulating and inhibitory factors, among which fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) play a central role. FGF-2 stimulates endothelial cell growth and migration and enhances angiogenesis, both in vitro and in vivo. FGF-2 binds to a specific receptor (FGF R1) at the surface of endothelial cells. In addition to its extracellular effects, FGF-2 exerts intracellular effects that seem to be independent from tyrosine kinase-type receptors. FGF-2 is produced by several tumor types, including brain tumors, skin tumors, and fibrosarcomas. FGF-2 may play a pivotal role in angiogenesis in these tumors.
Animals↗
Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization.
Platelet factor 4 (PF-4) inhibits angiogenesis in vitro and in vivo. The mechanism of inhibition is poorly understood. We have investigated the mechanism of inhibition by examining the interaction of PF-4 and the fibroblast growth factor-2 (FGF-2)/fibroblast growth factor receptor (FGFR) system. PF-4 inhibited the binding of FGF-2 to high-affinity and low-affinity binding sites in murine microvascular endothelial cells (LEII cells) and proliferation. Maximum inhibition of binding to endothelial FGF receptors was observed at PF-4 concentrations between 5 and 10 microg/mL (half maximum inhibition at 0.6 micro/mL), and proliferation was completely inhibited at 2 microg/mL. At this concentration, PF-4 reduced internalization of 125I-FGF-2 by threefold and delayed degradation. To gain insight into the mechanism of inhibition, we have analyzed the interaction of PF-4 with FGF-2/FGFR by using mutant heparan sulfate-deficient Chinese hamster ovary (CHO) cells transfected with the FGFR-1 cDNA (CHOm-FGFR-1) and by examining the direct interaction with FGF-2. In the absence of heparin, PF-4 inhibited binding of 125I-FGF-2 to CHOm-FGFR-1 cells in a concentration-dependent manner, although not completely. In the presence of heparin, PF-4 abolished totally the stimulatory effect of heparin. Furthermore, PF-4 complexed to FGF-2 and inhibited endogenous or heparin-induced FGF-2 dimerization. These results indicate that PF-4 interacts with FGF-2 by complex formation, inhibiting FGF-2 dimerization, binding to FGF receptors, and internalization. This mechanism most likely contributes to the antiangiogenic properties of PF-4.
Animals↗
Biology and physiopathology of angiogenesis: the 1997 Philippe Laudat Conference.
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Journal Article↗
New insights in the biology of fibroblast growth factor-2.
Fibroblast growth factor (FGF)-2 stimulates endothelial cell proliferation and is a potent angiogenic molecule in vitro and in vivo. In this review, we have focused on recent findings that relate to the mechanism of action and function of FGF-2. FGF-2 is expressed as four different isoforms: one 18 kDa FGF-2 form that is mainly cytoplasmic and three high molecular weight (HMW) FGF-2 forms that are preferentially localized in the nucleus. It has been demonstrated that these different isoforms lead to specific cellular phenotypes when expressed in cells. HMW FGF-2 controls proliferation by a receptor-independent mechanism, whereas 18 kDa FGF-2 stimulates migration by autocrine receptor activation. Intracellularly, HMW FGF-2 may directly associate with molecules that are involved in growth control. The action of FGF-2 at the cell surface may be altered by angiogenic inhibitors. Angiogenic inhibitors may directly interfere with FGF receptor activation or downstream signaling and thus inhibit FGF activity.
Journal Article↗
[Angiogenesis and neoangiogenesis].
Angiogenesis, the development of new capillary networks from the normal vasculature, is a fundamental process during embryogenesis. In adulthood, angiogenesis contributes to corpus luteum formation, placental implantation and wound healing and is also required in some pathological conditions such as several intraocular syndromes, growth of solid tumors, and metastasis. Many factors are involved in the regulation of neovascularisation among which FGF-2 (fibroblast growth factor-2) and VEGF (vascular endothelial growth factor) are considered as key inducers. Their biological activity is highly controlled by extracellular matrix components and angiostatic factors. Better understanding of the molecular mechanisms regulating angiogenesis should contribute to the development of new molecules to be used for the treatment of neovascularisation-linked diseases.
Angiogenesis Inducing Agents↗
French angiogenesis research network.
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Journal Article↗
Biological roles of fibroblast growth factor-2.
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Animals↗