Trends in Pharmacological Sciences
ReviewFGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition
Section snippets
FGF ligands and receptors
Basic fibroblast growth factor [bFGF (also known as FGF-2)] was the first pro-angiogenic molecule to be identified 5. At present, the FGF family is known to contain at least 20 factors, which are ∼30–70% identical in their primary amino acid sequences. The classical FGFs, FGF-1 and FGF-2, lack cytoplasmic sequences for extracellular export, in contrast to most growth factors that are secreted from their producer cells. The apparent lack of regulated FGF export has been an obstacle in the wide
Signal transduction induced by FGF and VEGF in different model assays
FGF, as well as VEGF, stimulate survival, proliferation, migration and differentiation of primary and stable endothelial cells, although the efficiencies of transduction of these responses are dependent on the type of endothelial cell line. The signalling pathways activated by FGFR-1 have been the most extensively studied and are summarized in Table 1. Analysis of VEGFR signalling has led to the conclusion that, although the affinity for VEGF binding is approximately tenfold higher for VEGFR-1
Therapeutic modulation of angiogenesis
It is now well established that tumour progression is angiogenesis dependent. Many tumour celllines secrete VEGF in vitro and VEGF mRNA levels are increased in most human tumours. Furthermore, both FGF-2 and VEGF are elevated in the serum of individuals with a variety of tumours 47. Other diseases characterized by excessive angiogenesis include diabetic retinopathy and rheumatoid arthritis. Intense research in the past few years has been focused on developing inhibitors of FGF and VEGF action
Conclusion and perspectives
One of the major challenges to researchers in the angiogenesis field has been to identify the crucial signal transduction pathway by which FGF and VEGF modulate angiogenesis. Cell culture models have provided a plethora of data regarding FGF and VEGF signal transduction pathways and their physiological role; however, it is also apparent that most of these pathways are also used by growth factors that are not angiogenic. The future lies in identifying the crucial genes activated by the FGF and
Acknowledgements
Work in our laboratory is supported by grants from the Association for International Cancer Research (AICR), Swedish Cancer Society, Novo Nordisk Foundation and The Göran Gustafsson Foundation.
Glossary
- CGP41251
- N-benzoylstaurosporine
- PD98059
- 2′-amino-3′-methoxyflavone
- PTK787/ZK22584
- 1-[4-chloroanilino]-4-[4-pyridylmethyl]phthalazine succinate
- SU5416
- 3-[(2,4-dimethylpyrrol-5-yl)methylidene]-indolin-2-one
- SU6668
- (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid
- ZD4190
- N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]quinazolin-4-amine
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