Review
FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition

https://doi.org/10.1016/S0165-6147(00)01676-XGet rights and content

Abstract

Angiogenic growth factors such as fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs) are currently targets of intense efforts to inhibit deregulated blood vessel formation in diseases such as cancer. FGFs and VEGFs exert their effects via specific binding to cell surface-expressed receptors equipped with tyrosine kinase activity. Activation of the receptor kinase activity allows coupling to downstream signal transduction pathways that regulate proliferation, migration and differentiation of endothelial cells. Inhibitors of FGF and VEGF signalling are currently in clinical trials. In this article, the current knowledge of FGF- and VEGF-induced signal transduction that leads to specific biological responses will be summarized. Furthermore, the manner in which this knowledge is being exploited to regulate angiogenesis will be discussed.

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

References (80)

  • M Dougher-Vermazen

    Biological activity and phosphorylation sites of the bacterially expressed cytosolic domain of the KDR VEGFreceptor

    Biochem. Biophys. Res. Commun.

    (1994)
  • M Clauss

    The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis

    J. Biol. Chem.

    (1996)
  • B.P Eliceiri

    Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability

    Mol. Cell

    (1999)
  • A Sorokin

    Internalization of fibroblast growth factor receptor is inhibited by a point mutation at tyrosine 766

    J. Biol. Chem.

    (1994)
  • H Xu

    Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteins

    J. Biol. Chem.

    (1998)
  • H Kouhara

    A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway

    Cell

    (1997)
  • J.F Reilly

    Association of fibroblast growth factor receptor 1 with the adaptor protein Grb14. Characterization of a new receptor binding partner

    J. Biol. Chem.

    (2000)
  • S Kanda

    Phosphatidylinositol 3′-kinase-independent p70 S6 kinase activation by fibroblast growth factor receptor-1 is important for proliferation but not differentiation of endothelial cells

    J. Biol. Chem.

    (1997)
  • P Maher

    p38 mitogen-activated protein kinase activation is required for fibroblast growth factor-2-stimulated cell proliferation but not differentiation

    J. Biol. Chem.

    (1999)
  • S.A Cunningham

    Interactions of FLT-1 and KDR with phospholipase C γ: identification of the phosphotyrosine binding sites

    Biochem. Biophys. Res. Commun.

    (1997)
  • L.W Wu

    VRAP is an adaptor protein that binds KDR, a receptor for vascular endothelial cell growth factor

    J. Biol. Chem.

    (2000)
  • C Wheeler-Jones

    Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/44 mitogen-activated protein kinase

    FEBS Lett.

    (1997)
  • L.W Wu

    Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation

    J. Biol. Chem.

    (2000)
  • H.P Gerber

    Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation

    J. Biol. Chem.

    (1998)
  • S Dimmeler

    Phosphorylation of the endothelial nitric oxide synthase at Ser-1177 is required for VEGF-induced endothelial cell migration

    FEBS Lett.

    (2000)
  • H He

    Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src

    J. Biol. Chem.

    (1999)
  • S Rousseau

    Vascular endothelial growth factor (VEGF)-driven actin-based motility is mediated by VEGFR2 and requires concerted activation of stress-activated protein kinase 2 (SAPK2/p38) and geldanamycin-sensitive phosphorylation of focal adhesion kinase

    J. Biol. Chem.

    (2000)
  • H Abedi et al.

    Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells

    J. Biol. Chem.

    (1997)
  • A Parenti

    Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-related kinase 1/2 activation in postcapillary endothelium

    J. Biol. Chem.

    (1998)
  • J Hood et al.

    Protein kinase G mediates vascular endothelial growth factor-induced Raf-1 activation and proliferation in human endothelial cells

    J. Biol. Chem.

    (1998)
  • P Carmeliet

    Mechanisms of angiogenesis and arteriogenesis

    Nat. Med.

    (2000)
  • G.D Yancopoulos

    Vascular-specific growth factors and blood vessel formation

    Nature

    (2000)
  • R.S Kerbel

    Tumor angiogenesis: past, present and the near future

    Carcinogenesis

    (2000)
  • Y Shing

    Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor

    Science

    (1984)
  • D.M Ornitz

    FGFs, heparan sulfate and FGFRs: complex interactions essential for development

    BioEssays

    (2000)
  • D.E Johnson et al.

    Structural and functional diversity in the FGF receptor multigene family

    Adv. Cancer Res.

    (1993)
  • G Szebenyi et al.

    Fibroblast growth factors as multifunctional signaling factors

    Int. Rev. Cytol.

    (1999)
  • C.X Deng

    Murine FGFR-1 is required for early postimplantation growth and axial organization

    Genes Dev.

    (1994)
  • X Xu

    Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction

    Development

    (1998)
  • R Dono

    Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice

    EMBO J.

    (1998)
  • Cited by (854)

    View all citing articles on Scopus
    View full text