Document Top

Back to VEGF and angiogenesis

VEGF(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour): the predominant regulator of angiogenesis(The growth of new blood vessels from pre-existing vessels)

Among the many factors implicated in angiogenesis, VEGF has been identified as the most potent and predominant. The scope of scientific research involving VEGF continues to grow exponentially. From 1995–2005, the number of VEGF-related abstracts presented at the annual meeting of ASCO increased 50-fold, highlighting the increased focus in research upon the role of VEGF in oncology.

What is VEGF?

VEGF (also known as VEGF-A, but commonly referred to simply as VEGF) stands for ‘vascular endothelial growth factor(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour)’. This protein plays an important role in angiogenesis. As its name suggests, VEGF stimulates vascular endothelial cell growth, survival and proliferation(The reproduction of cells by multiplication of parts). As seen in preclinical models, VEGF has been shown to facilitate survival of existing vessels, increase vessel permeability, and stimulate new vessel growth.1–7


The VEGF family of proteins

VEGF is a member of a family of six structurally related proteins (see table) that regulate the growth and differentiation of multiple components of the vascular system, especially blood and lymph(A transparent, usually slightly yellow, often opalescent liquid found within the lymphatic vessels, and collected from tissues in all parts of the body and returned to the blood via the lymphatic system) vessels. The angiogenic effects of the VEGF family are thought to be primarily mediated through the interaction of VEGF with VEGFR-2.1,2

VEGF family of proteins

VEGF family members Receptors Functions
VEGF (VEGF-A)

VEGFR-1, VEGFR-2, neuropilin-1

 Angiogenesis
Vascular maintenance
VEGF-B

VEGFR-1

Not established
VEGF-C

VEGFR-2, VEGFR-3

 Lymphangiogenesis
VEGF-D

VEGFR-2, VEGFR-3

Lymphangiogenesis

VEGF-E (viral factor)

VEGFR-2

 Angiogenesis
PlGF

VEGFR-1, neuropilin-1

 Angiogenesis
Inflammation

There are four major isotypes of VEGF-A (VEGF), each coded for by a different portion of the VEGF gene. These isotypes are VEGF121, VEGF165, VEGF189, and VEGF206.8–11 Although these isotypes behave identically in solution, they differ in their ability to bind heparin and the extracellular matrix.12

The VEGF pathway

VEGF plays a central role in angiogenesis throughout tumour(An abnormal growth of cells, forming a mass of tissue) development

The production of VEGF is stimulated by upstream activators, including environmental cues, growth factors, oncogenes, cytokines(Small cell-signalling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system) and hormones. The binding of VEGF to its receptors on the surface of endothelial cells activates intracellular TKs, triggering multiple downstream signals that promote angiogenesis. Although there are multiple variants of both VEGF and its receptor(Proteins located on the cell surface. When a specific molecule called a ligand binds to a receptor, signalling pathways are activated), the angiogenic effects of this pathway are primarily mediated through the interaction of VEGF-A (the most common variant, often referred to simply as VEGF) with VEGFR-2. Other non-VEGF factors are thought to play a secondary role in angiogenesis, though many of these factors may also impact additional nonangiogenic pathways.1,2,13–15

More specifically, a number of interrelated signals and processes have been identified that lead to the production of VEGF and, subsequently, to neovascularisation(The formation of functional microvascular networks with red blood cell perfusion) of a tumour

  • VEGF is produced in response to a variety of environmental and cellular stimuli.
  • An imbalance between pro- and anti-angiogenic factors can turn on the ‘angiogenic switch(A shift of the angiogenic balance to the pro-angiogenic state)’.
  • VEGF binds to the VEGF family of receptors.
  • Receptor binding initiates a downstream signalling cascade.

These are discussed in detail below.

Environmental and cellular triggers of VEGF

VEGF production and subsequent angiogenesis can be triggered by a number of factors, including both genes and gene products, in the cellular microenvironment. To learn more about individual stimuli, see below.

Environmental and cellular triggers of VEGF

VEGF triggers Description Factors involved
Hypoxia Lack of oxygen in the tumour Microenvironment
 HIF-1α2
HIF-1β2
Oncogenes
Tumour suppressor genes
 Genes that stimulate or suppress tumour formation c-Src oncogene16
Bcr-Abl oncogene17
Ras oncogene18–20
p53 tumour suppressor gene21,22
Cellular receptors Cellular receptors EGFR23
HER-224,25
IGF-IR26,27
Other growth factors and cytokines Proteins secreted by cells that stimulate cellular signalling COX-228
PDGF29

Hypoxia triggers VEGF expression

Without an independent blood supply, tumours obtain oxygen and other nutrients by diffusion only, and typically cannot grow more than 2mm3 in size. Thus, a growing tumour without sufficient vasculature will have hypoxic areas (i.e. areas lacking in oxygen). In response to hypoxic conditions, tumours secrete VEGF in order to recruit new vasculature, which then provides a supply of oxygen.31

Hypoxia remains an important trigger of VEGF expression even once a tumour becomes vascularised. As the tumour grows, it continually outgrows its existing blood supply, leaving a rim of necrotic(Pertaining to the death of living tissue through disease, injury or interruption of the blood supply) and hypoxic tissue. The tumour responds by upregulating VEGF gene expression, primarily through the activity of HIF-1, a protein consisting of two subunits (HIF-1α and HIF-1β).2,3 Recent research by Mizukami and colleagues (in colon cancer cells) suggests that an alternative mechanism for hypoxic induction of VEGF through a pathway involving PI3K and c-Myc may also play a role.32

Oncogenes and tumour suppressor genes(Genes that are involved in growth inhibition; following mutation, it may no longer suppress cell growth and can contribute to malignant transformation) trigger VEGF expression

Oncogenes (genes that contribute to the production of a cancer) and tumour suppressor genes (genes encoding a protein that normally suppresses tumour formation) are associated with increased VEGF production. Oncogenes are generally mutated forms of proto-oncogenes (normal cellular genes capable of transforming a cell when activated). Some examples of oncogenes and tumour suppressor genes include

  • c-Src is a proto-oncogene(A normal gene which, when altered by mutation, becomes an oncogene that can contribute to cancer. Proto-oncogenes may have many different functions in the cell. Some proto-oncogenes provide signals that lead to cell division. Other proto-oncogenes regulate programmed cell death) that appears to directly stimulate VEGF expression. c-Src signal transduction(The process by which an extracellular signaling molecule activates a membrane receptor that in turn alters intracellular molecules creating a response) may also indirectly regulate VEGF expression through stimulation of additional factors.16,33,34
  • Bcr-Abl is an oncogene(A gene that has the potential to cause cancer when its normal methods of regulation fail, e.g. due to a mutation) formed from fusion of two proto-oncogenes, resulting in CML.35 A preclinical study in tumour cell lines showed that transfection of Bcr-Abl caused an increase in VEGF expression, whereas blocking the function of Bcr-Abl reduced VEGF expression.17
  • Ras oncogene: Ras proteins are part of the signalling cascade of growth factor-induced angiogenesis. The genes that encode for Ras proteins have been associated with induction of VEGF expression in many solid tumours, including pancreatic, colorectal and non-small cell lung cancers.18–20
  • p53 tumour suppressor gene: Dysregulation of p53, normally a regulator of the cell cycle and trigger of apoptosis(The process of programmed cell death that may occur in multicellular organisms) in damaged cells, has been implicated in the pathology of solid malignancies, including colorectal, breast and endometrial carcinomas. Genetic alteration of tumour suppressor genes, including p53, has been shown to induce VEGF production.21,22

Cellular receptors trigger VEGF expression

Some receptors on the surface of cancer cells may induce increased expression of VEGF, including

  • EGFR activation: also known as HER-1 and ErbB1, EGFR is expressed or overexpressed in a wide variety of common solid tumours, including breast, lung, colorectal, prostate, renal and ovarian cancers. Among other oncogenic effects, the EGFR signalling pathway results in increased VEGF production.23,36–38
  • HER-2 overexpression(Excessive expression of a gene or its protein product): also known as ErbB2, HER-2 has been associated with increased VEGF production in multiple solid tumour types.24,25 In a study of 611 primary breast cancer patients, Konecny and colleagues demonstrated that HER-2/neu-positive tumours expressed significantly more VEGF than HER-2/neu-negative tumours.39 Furthermore, overexpression of both HER-2/neu and VEGF was correlated with the poorest clinical outcome in the study.
  • IGF-1R activation: this receptor is associated with increased VEGF production in breast, endometrial, pancreatic and colorectal cancers.26,27

Other growth factors and cytokines trigger VEGF expression

VEGF, a growth factor and cytokine, may be produced in response to other growth factors and cytokines, including

  • COX-2: the link between COX-2 overexpression and angiogenesis has been extensively documented. COX-2 has also been shown to mediate VEGF expression in numerous cell lines, but this effect is not evident in all tumours28,40–42
  • PDGF: PDGF modulates angiogenesis in vivo by promoting endothelial cell survival and vascular maturation through the recruitment of pericytes and vascular smooth muscle cells.43 Recent work by Ferrara et al. established a link between PDGF and recruitment of VEGF-producing stromal fibroblasts in a model deficient of tumour-derived VEGF.29 The results suggest host-derived VEGF also plays an important role in angiogenesis, along with tumour-generated VEGF.

VEGF expression and the angiogenic switch

Angiogenesis is tightly regulated by a number of pro- and anti-angiogenic molecules. Under normal conditions, there is a delicate balance between pro- and anti-angiogenic factors, and angiogenesis does not occur. However, during tumour growth, a variety of environmental and cellular triggers lead to overexpression of pro-angiogenic factors. These factors, including VEGF, can tip the balance toward angiogenesis.3

The moment at which a tumour begins to overexpress pro-angiogenic factors, such as VEGF, is generally referred to as the angiogenic switch. The switch overwhelms the delicate balance of pro- and anti-angiogenic factors to grow new vasculature, thereby facilitating the growth of the tumour.3

Visualising the angiogenic switch

These images depict neovascularisation in a rat tumour model over 12 days following implantation of a tumour.

 VEGF has a predominant role throughout tumour development

VEGF contributes to tumour growth in several important ways.1–7,44,45

  • Facilitates survival of existing vessels.
  • Increases vessel permeability.
  • Stimulates new vessel growth.
  • May prevent immune response to tumours.

The mechanisms from which the various functions of VEGF in endothelial cells arise are shown in the table below.2

The various functions of VEGF

Function Mechanism
Proliferation

Activation of mitogen-activated protein kinases
Permeability
 Vesicovascular organelles
Endothelial fenestrations
Opening of junctions between adjacent endothelial cells
Invasion Induction of metalloproteinases uPA, uPAR, TTPA
Migration Activation of FAK, p38, nitric oxide
Survival Induction of PI3K/Akt, Bcl2, A1, survivin, XIAP, or FAK
Inhibition of caspases
Activation Upregulation of integrin expression
Alteration of cell cytoskeleton

References

  1. Ferrara N. Endocr Rev 2004;25:581–611.
  2. Hicklin DJ, Ellis LM. J Clin Oncol 2005;23:1011–27.
  3. Bergers G, Benjamin LE. Nat Rev Cancer 2003;3:401–10.
  4. Jain RK. Nat Med 2001;7:987–9.
  5. Jain RK. Science 2005;307:58–62.
  6. Bates DO, Curry FE. Am J Physiol 1996; H2520– H2528.
  7. Gerber HP, Ferrara N. Cancer Res 2005;65:671–80.
  8. Relf M, LeJeune S, Scott PAE, et al. Cancer Res 1997;57:963–9.
  9. Stimpfl M, Tong D, Fasching B, et al. Clin Cancer Res 2002;8:2253–9.
  10. Tischer E, Mitchell R, Hartman T, et al. J Biol Chem 1991;266:11947–54.
  11. Houck KA, Ferrara N, Winer J, et al. Mol Endocrinol 1991;5:1806–14.
  12. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. J Biol Chem 1992;267:26031–7.
  13. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Nat Rev Drug Discov 2004;3:391–400.
  14. Kryczek I, Lange A, Mottram P, et al. Cancer Res 2005;65:465–72.
  15. Guleng B, Tateishi K, Ohta M, et al. Cancer Res 2005;65:5864–71.
  16. Ellis LM, Staley CA, Liu W, et al. J Biol Chem 1998;273:1052–7.
  17. Ebos JML, Tran J, Master Z, et al. Mol Cancer Res 2002;1:89–95.
  18. Ikeda N, Nakajima Y, Sho M, et al. Cancer 2001;92:488–99.
  19. Konishi T, Huang CL, Adachi M, et al. Int J Oncol 2000;16:501–11.
  20. Okada F, Rak JW, St. Croix B, et al. Proc Natl Acad Sci USA 1998;95:3609–14.
  21. Bouvet M, Ellis LM, Nishizaki M, et al. Cancer Res 1998;58:2288–92.
  22. Fujisawa T, Watanabe J, Kamata Y, Hamamo M, Hata H, Kuramoto H. Exp Mol Pathol 2003;74:276–81.
  23. Maity A, Pore N, Lee J, et al. Cancer Res 2000;60:5879–86.
  24. Kumar R, Yarmand-Bagheri R. Semin Oncol 2001;28(Suppl. 16):27–32.
  25. Yang W, Klos K, Yang Y, Smith TL, Shi D, Yu D. Cancer 2002;94:2855–61.
  26. Reinmuth N, Liu W, Fan F, et al. Clin Cancer Res 2002;8:3259–69.
  27. Warren RS, Yuan H, Matli MR, Ferrara N, Donner DB. J Biol Chem 1996;271:29483–8.
  28. Joo YE, Rew JS, Seo YH, et al. J Clin Gastroenterol 2003;37:28–33.
  29. Dong J, Grunstein J, Tejada M, et al. EMBO J 2004;23:2800–10.
  30. Hellman S. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2001. p. 265–89.
  31. Shweiki D, Itin A, Soffer D, Keshet E. Nature 1992;359:843–5.
  32. Mizukami Y, Fujiki K, Duerr EM, et al. J Biol Chem 2006;20:13957–63.
  33. He H, Venema VJ, Gu X, et al. J Biol Chem 1999;274:25130–5.
  34. Fleming RYD, Ellis LM, Parikh NU, et al. Surgery 1997;122:501–7.
  35. Goldman JM, Melo JV. N Engl J Med 2003;349:1451–64.
  36. Arteaga CL. Oncologist. 2002;7(Suppl. 4):31–9.
  37. Salomon DS, Brandt R, Ciardiello F, et al. Crit Rev Oncol Hematol 1995;19:183–232.
  38. Yarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol 2001;2:127–37.
  39. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res 2004;10:1706–16.
  40. Yao M, Kargman S, Lam EC, et al. Cancer Res 2003;63:586–92.
  41. Costa C, Soares R, Reis-Filho JS, et al. J Clin Pathol 2002;55:429–34.
  42. Aoki T, Nagakawa Y, Tsuchida A, et al. Oncol Rep 2002;9:761–5.
  43. Cao R, Brakenhielm E, Li X, et al. FASEB J 2002;16:1575–83.
  44. Gabrilovich DI, Chen HL, Girgis KR, et al. Nat Med 1996;2:1096–103.
  45. Barbera-Guillem E, Nyhus JK, Wolford CC, Friece CR, Sampsel JW. Cancer Res 2002;62:7042–9.

Back to VEGF and angiogenesis Back to top

x

You are now leaving the www.avastin.net website. Links to all external sites are provided as a resource to our visitors. Hoffmann-La Roche Inc. ("Roche") accepts no responsibility for the content of these sites. Roche does not control these sites, and the opinions, claims, or comments expressed on these sites should not be attributed to Roche, except where indicated. We recommend that you consult with your physician or other healthcare provider to obtain more information about any Roche prescription medication.

OK Cancel