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Landmark papers in VEGF research

From early literature exploring central research questions to today’s most cited review articles, the history of research on VEGF in angiogenesis in tumour biology is marked by a number of seminal papers.

 
Neoangiogenesis
Original image from Ide et al. (1939) showing an extensive vascular network in transplanted rabbit epithelioma.

During the 1930s, the first observations of neoangiogenesis were reported in animal models.

  • Ide AG, Baker NH, Warren SL. Vascularization of the Brown Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am J Roentgenol 1939;42:891–9.
  • Clark ER, Clark EL. Observations on living preformed blood vessels as seen in a transparent chamber inserted into the rabbit ear. Am J Anat 1932;49:441–7.
 

It was more than 60 years ago that tumours were first demonstrated to actively attract new blood vessels, a process now known as tumour angiogenesis.

  • Algire GH, Chalkley HW, Legallais FY, Park HD. Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst 1945;6:73–85.
   
Tumour angiogenesis

Depiction of how tumours acquire vital nutrients in both prevascular and vascular states. Here, tumour angiogenesis factor (TAF) is hypothesised to be responsible for this transformation. Based on Folkman 1971.

The concept of angiogenesis inhibition as a therapeutic strategy in cancer (and other ‘angiogenesis-dependent’ diseases) was first introduced in the pivotal review by Folkman in 1971. The concepts presented in this review were strengthened by two studies showing tumours produce factors stimulating blood vessel growth and are dependent on angiogenesis for progressive growth.

  • Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6.
  • Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971;133:275–88.
  • Gimbrone MA Jr, Leapman SB, Cotran RS, Folkman J. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 1972;136:261–76.
 

In the 1980s, VEGF identified as a specific and important regulator of vascular growth and function.

  • Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219:983–5.
  • Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic molecule. Science 1989;246:1306–9.
  • Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989;246:1309–12.
  

The development of knockout mice and the cloning of VEGF further highlighted the importance of VEGF to angiogenesis.

  • Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435–9.
  • Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality by targeted inactivation of the VEGF gene. Nature 1996;380:439–42.
  • Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989;161:851–8.
  

The growth inhibition of human tumour xenografts by an anti-human VEGF antibody represents the first preclinical example of targeted anti-angiogenic therapy.

  • Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841–4.
 
Normalisation of tumour vasculature by anti-angiogenesis therapy
Reprinted by permission from Macmillan Publishers Ltd: Nat Med 7(9):987–9, copyright 2001.

A combination of anti-angiogenic therapy and chemotherapy is proposed as a strategy to maximise the efficacy of both therapies through the normalisation of tumour vasculature, improving the delivery of chemotherapy.

  • Jain RK. Normalizing tumor vasculature with antiangiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7:987–9.
 

Other suggested reading

  • Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27–31.
  • Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995;146:1029–39.
  • Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989;161:851–58.
  • Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6.
  • Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011–27.
  • Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.
 

Adapted from http://www.nature.com/focus/angiogenesis/classics/establish.html (accessed 2009-11-02)