Antiangiogenesis, Anti-VEGF(R) and Outlook

  • Iver Petersen
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 176)


Tumor angiogenesis and antiangiogenesis has moved from an exotic research topic into clinical practice defining a new and promising avenue of targeted cancer therapy. Starting with a historical perspective on tumor angiogenesis, this review provides the basic concepts and classification of angiogenesis inhibition. Focusing primarily on vascular endothelial growth factor (VEGF), the biological activity and regulation of the gene expression of VEGF, its isoforms, and the receptors are summarized. Furthermore, naturally occurring modulators are listed, an overview on angiogenesis inhibitors in clinical trails is provided, and finally a brief outlook is given on this fascinating and rapidly evolving field of oncology.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Achen MG, Williams RA, Minekus MP, Thornton GE, Stenvers K, Rogers PA, Lederman F, Roufail S, Stacker SA (2001) Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis. J Pathol 193:147–154PubMedCrossRefGoogle Scholar
  2. Bagri A, Tessier-Lavigne M (2002) Neuropilins as Semaphorin receptors: in vivo functions in neuronal cell migration and axon guidance. Adv Exp Med Biol 515:13–31PubMedGoogle Scholar
  3. Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, Karkkainen MJ, Alitalo K, Stacker SA, Achen MG (2001) The specificity of receptor binding by vascular endothelial growth factord is different in mouse and man. J Biol Chem 1276:19166–19171CrossRefGoogle Scholar
  4. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E (1999) Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 103:159–165PubMedGoogle Scholar
  5. Boehm T, Folkman J, Browder T, O’Reilly MS (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 27390:404–407CrossRefGoogle Scholar
  6. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583PubMedCrossRefGoogle Scholar
  7. Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F, Nemery B, Dewerchin M, Van Veldhoven P, Plate K, Moons L, Collen D, Carmeliet P (2002) Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8:702–710PubMedGoogle Scholar
  8. Ellis LM (2004) Angiogenesis and its role in colorectal tumor and metastasis formation. Semin Oncol 31:3–9PubMedCrossRefGoogle Scholar
  9. Fayette J, Soria JC, Armand JP (2005) Use of angiogenesis inhibitors in tumour treatment. Eur J Cancer 41:1109–1116PubMedCrossRefGoogle Scholar
  10. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611PubMedCrossRefGoogle Scholar
  11. Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 15161:851–858CrossRefGoogle Scholar
  12. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676PubMedCrossRefGoogle Scholar
  13. Folkman J, Merler E, Abernathy C, Williams G (1971a) Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1133:275–288CrossRefGoogle Scholar
  14. Folkman J (1971b) Tumor angiogenesis: therapeutic implications. N Engl J Med 18285:1182–1186Google Scholar
  15. Folkman J, Klagsbrun M (1987) Vascular physiology. A family of angiogenic peptides. Nature 329:671–672PubMedCrossRefGoogle Scholar
  16. Gerber HP, Dixit V, Ferrara N (1998) Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 22273:13313–13316CrossRefGoogle Scholar
  17. Gupta K, Zhang J (2005) Angiogenesis: a curse or cure? Postgrad Med J 81:236–242PubMedCrossRefGoogle Scholar
  18. He Y, Karpanen T, Alitalo K (2004) Role of lymphangiogenic factors in tumor metastasis. Biochim Biophys Acta 41654:3–12Google Scholar
  19. Huang K, Andersson C, Roomans GM, Ito N, Claesson-Welsh L (2001) Signaling properties of VEGF receptor-1 and-2 homo-and heterodimers. Int J Biochem Cell Biol 33:315–324PubMedCrossRefGoogle Scholar
  20. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 3350:2335–2342CrossRefGoogle Scholar
  21. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K (2004) Vascular endothelial growth factor C is required for sprouting of first lymphatic vessels from embryonic veins. Nat Immunol 5:74–80PubMedCrossRefGoogle Scholar
  22. Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739PubMedCrossRefGoogle Scholar
  23. Klagsbrun M, Takashima S, Mamluk R (2002) The role of neuropilin in vascular and tumor biology. Adv Exp Med Biol 515:33–48PubMedGoogle Scholar
  24. Ku DD, Zaleski JK, Liu S, Brock TA (1993) Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol 265:H586–H592PubMedGoogle Scholar
  25. Matsumoto T, Claesson-Welsh L (2001) VEGF receptor signal transduction. Sci STKE 2001 Dec 11: RE21Google Scholar
  26. Mole DR, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Regulation of HIF by the von Hippel-Lindau tumour suppressor: implications for cellular oxygen sensing. IUBMB Life 52:43–47PubMedCrossRefGoogle Scholar
  27. Muhsin M, Graham J, Kirkpatrick P (2004) Bevacizumab. Nat Rev Drug Discov 3:995–996PubMedCrossRefGoogle Scholar
  28. Nyberg P, Xie L, Kalluri R (2005) Endogenous inhibitors of angiogenesis. Cancer Res 1565:3967–3979CrossRefGoogle Scholar
  29. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 2488:277–285CrossRefGoogle Scholar
  30. Park JE, Chen HH, Winer J, Houck KA, Ferrara N (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 14269:25646–25654Google Scholar
  31. Posey JA, Ng TC, Yang B, Khazaeli MB, Carpenter MD, Fox F, Needle M, Waksal H, LoBuglio AF (2003) A phase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma. Clin Cancer Res 9:1323–1332PubMedGoogle Scholar
  32. Rundhaug JE (2005) Matrix metalloproteinases and angiogenesis. J Cell Mol Med 9:267–285PubMedCrossRefGoogle Scholar
  33. Saharinen P, Tammela T, Karkkainen MJ, Alitalo K (2004) Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol 25:387–395PubMedCrossRefGoogle Scholar
  34. Semenza G (2002) Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 64:993–998PubMedCrossRefGoogle Scholar
  35. Serini G, Valdembri D, Bussolino F (2005) Integrins and angiogenesis: a sticky business. Exp Cell Res 312:651–658PubMedCrossRefGoogle Scholar
  36. Tammela T, Enholm B, Alitalo K, Paavonen K (2005) The biology of vascular endothelial growth factors. Cardiovasc Res 1565:550–563CrossRefGoogle Scholar
  37. Tandle A, Blazer DG 3rd, Libutti SK (2004) Antiangiogenic gene therapy of cancer: recent developments. J Transl Med 2:20CrossRefGoogle Scholar
  38. Yang R, Thomas GR, Bunting S, Ko A, Ferrara N, Keyt B, Ross J, Jin H (1996) Effects of vascular endothelial growth factor on hemodynamics and cardiac performance. J Cardiovasc Pharmacol 27:838–844PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  • Iver Petersen
    • 1
  1. 1.Institut für Pathologie Rudolf-Virchow-HausHumboldt-Universität BerlinBerlinGermany

Personalised recommendations