Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein with a molecular weight of approximately 45 kDa. It is the key mediator of angiogenesis (the formation of new blood vessels), and binds two VEGF receptors (VEGF receptor-1 and VEGF receptor-2), which are expressed on vascular endothelial cells. In healthy humans, VEGF promotes angiogenesis in embryonic development and is important in wound healing in adults. VEGF is the key mediator of angiogenesis in cancer, in which it is up-regulated by oncogene expression, a variety of growth factors and also hypoxia. Angiogenesis is essential for cancer development and growth: before a tumor can grow beyond 1–2 mm, it requires blood vessels for nutrients and oxygen. The production of VEGF and other growth factors by the tumor results in the ‘angiogenic switch’, where new vasculature is formed in and around the tumor, allowing it to grow exponentially. Tumor vasculature formed under the influence of VEGF is structurally and functionally abnormal. Blood vessels are irregularly shaped, tortuous, have dead ends and are not organized into venules, arterioles and capillaries. They are also leaky and hemorrhagic, which leads to high interstitial pressure. These characteristics mean that tumor blood flow is suboptimal, resulting in hypoxia and further VEGF production. This central role of VEGF in the production of tumor vasculature makes it a rational target for anticancer therapy.

Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev 1997;18:4–25.
Ferrara N: Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 2001;280:C1358–1366.
Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 2003;9:669–676.
Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N: Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 1992;267:26031–26037.
Keyt BA, Berleau LT, Nguyen HV, Chen H, Heinsohn H, Vandlen R, Ferrara N: The carboxyl-terminal domain (111–165) of vascular endothelial growth factor is critical for its mitogenic potency. J Biol Chem 1996;271:7788–7795.
Ferrara N: Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 2004;9(suppl 1):2–10.
Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992;359:843–845.
Banai S, Shweiki D, Pinson A, Chandra M, Lazarovici G, Keshet E: Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: Implications for coronary angiogenesis. Cardiovasc Res 1994;28:1176–1179.
Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK: Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 2001;61:6020–6024.
Thomas KA: Vascular endothelial growth factor, a potent and selective angiogenic agent. J Biol Chem 1996;271:603–606.
Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH: Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994;269:26988–26995.
Kendall RL, Wang G, DiSalvo J, Thomas KA: Specificity of vascular endothelial cell growth factor receptor ligand binding domains. Biochem Biophys Res Commun 1994;201:326–330.
Pepper MS, Ferrara N, Orci L, Montesano R: Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 1992;189:824–831.
Alon T, Hemo I, Itin A, Pe’er J, Stone J, Keshet E: Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995;1:1024–1028.
Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, Ferrara N: Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 1994;152:4149–4156.
Mandriota SJ, Seghezzi G, Vassalli JD, Ferrara N, Wasi S, Mazzieri R, Mignatti P, Pepper MS: Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells. J Biol Chem 1995;270:9709–9716.
Unemori EN, Ferrara N, Bauer EA, Amento EP: Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 1992;153:557–562.
Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP: Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998;92:4150–4166.
Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435–439.
Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996;380:439–442.
Kronenberg HM: Developmental regulation of the growth plate. Nature 2003;423:332–336.
Goede V, Schmidt T, Kimmina S, Kozian D, Augustin HG: Analysis of blood vessel maturation processes during cyclic ovarian angiogenesis. Lab Invest 1998;78:1835–1894.
Li J, Zhang Y-P, Kirsner RS: Angiogenesis in wound repair: Angiogenic growth factors and the extracellular matrix. Microsc Res Tech 2003;60:107–114.
Poon RT-P, Fan S-T, Wong J: Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001;19:1207–1225.
Brown LF, Guidi AJ, Schnitt SJ, Van De Water L, Iruela-Arispe ML, Yeo TK, Tognazzi K, Dvorak HF: Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin Cancer Res 1999;5:1041–1056.
Bergers G, Benjamin LE: Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003;3:401–410.
Folkman J: Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182–1186.
Ferrara N, Henzel WJ: Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989;161:851–858.
Ikeda E, Achen MG, Breier G, Risau W: Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 1995;270:19761–19766.
Kaelin WG Jr: The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res 2004;10:6290S–6295S.
Rak J, Yu JL, Klement G, Kerbel RS: Oncogenes and angiogenesis: Signaling three-dimensional tumor growth. J Investig Dermatol Symp Proc 2000;5:24–33.
O-charoenrat P, Rhys-Evans PH, Modjtahedi H, Eccles SA: The role of c-erbB receptors and ligands in head and neck squamous cell carcinoma. Oral Oncol 2002;38:627–640.
Masood R, Cai J, Zheng T, Smith DL, Hinton DR, Gill PS: Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors. Blood 2001;98:1904–1913.
Harmey JH, Bouchier-Hayes D: Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: implications for anti-angiogenic therapy. Bioessays 2002;24:280–283.
Tran J, Rak J, Sheehan C, Saibil SD, LaCasse E, Korneluk RG, Kerbel RS: Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem Biophys Res Commun 1999;264:781–788.
Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM: Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999;286:2511–2514.
Petterson A, Nagy JA, Brown LF, Sundberg C, Morgan E, Jungles S, Carter R, Krieger JE, Manseau EJ, Harvey SV, Eckelhoefer IA, Feng D, Dvorak AM, Mulligan RC, Dvorak HF: Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest 2000;80:99–115.
Netti PA, Hamberg LM, Babich JW, Kierstead D, Graham W, Hunter GJ, Wolf GL, Fischman A, Boucher Y, Jain RK: Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci USA 1999;96:3137–3142.
Jain RK: Molecular regulation of vessel maturation. Nat Med 2003;9:685–693.
Carmeliet P: Angiogenesis in health and disease. Nat Med 2003;9:653–660.
Dvorak HF: Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986;315:1650–1659.
Helmlinger G, Yuan F, Dellian M, Jain RK: Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation. Nat Med 1997;3:177–182.
Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 2001;7:987–989.
Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145–147.
Shen BQ, Stainton S, Li D, Pelletier N, Zioncheck TF: Combination of AvastinTM and Xeloda® synergistically inhibits colorectal tumor growth in a COLO205 tumor xenograft model. Proc Am Assoc Cancer Res 2004;45:508 (abstract 2203).
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