Document Top

Back to VEGF and angiogenesis

Growth and survival of tumour(An abnormal growth of cells, forming a mass of tissue) blood vessels

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

VEGF stimulates tumour angiogenesis

The binding of VEGF to receptors on endothelial cells initiates the creation of a vascular network, allowing tumours access to the oxygen and nutrients they need to grow and metastasise.1

VEGF is a survival factor for existing tumour vasculature

Endothelial cells require VEGF for their continued survival in immature blood vessels.2,3 In the absence of growth signals, endothelial cells undergo programmed cell death (apoptosis(The process of programmed cell death that may occur in multicellular organisms)). Upon pericyte(A connective tissue cell that occurs about small blood vessels) association with vascular endothelial cells (vascular maturation), VEGF is no longer required for survival.1,4

Formation of abnormal vasculature

The angiogenic switch(A shift of the angiogenic balance to the pro-angiogenic state) induces abnormal vasculature

VEGF is a potent permeability factor

VEGF stimulates vascular permeability in small blood vessels. The increased permeability causes the leakage of plasma proteins and the formation of an extravascular fibrin gel, providing a suitable environment for endothelial cell growth. In tumours, high levels of VEGF result in vasculature that is excessively permeable and leaky, leading to increased interstitial pressure(Fluid pressure pertaining to parts or interspaces of a tissue), and, consequently, uneven delivery of nutrients and oxygen to the tumour.6,7 Increased permeability of tumour vessels can also lead to the accumulation of fluid around the tumour, known as ascites.8

Irregularities in tumour vasculature

The pathological beginnings of tumour vasculature are reflected in its abnormal phenotype(The visible characteristics of an organism that are produced by the interaction of the organism’s genes and the environment). Whereas normal vasculature quickly matures and stabilises, tumour vasculature is characterised by structural and functional abnormalities. These defects, due in large part to VEGF, include tortuousness, hyperpermeability and lack of structure-giving pericytes. Together, these abnormalities create an environment that is favourable to tumour growth.6

Interstitial pressure in tumours

Tumours are not composed entirely of malignant cells. In fact, less than half of a tumour's volume may be cancer cells, 1–10% may be blood vessels, and the remainder is interstitium, a collagen-rich matrix that surrounds cancer cells and separates them from the vasculature.9,10

Tumour vasculature is leaky due to gaps between endothelial cells and openings within the cells themselves.11 Because of the hyperpermeable nature of VEGF-induced vasculature, fluid can leak from tumour vessels into the interstitium.6,9 The result is remarkably high interstitial pressure throughout the interior of a tumour, while pressure in the outermost areas remains at close to normal levels.9 By contrast, pressure in veins (the predominant vessels in tumours) is reduced in tumour veins compared with veins in normal tissue. Thus, there is a dual effect of increased interstitial pressure and decreased vascular pressure in tumours.12

High interstitial pressure has been demonstrated in a variety of tumour types, as shown below.9

High interstitial pressure in various tumour types

Types of tissue Number of patients Mean pressure

Normal breast

 8
 0.0

Normal skin

 5 0.4

RCC

 1 38.0

Cervical carcinoma

 26 22.8

Colorectal liver metastases

 8 21.0

Head and neck carcinoma

 27 19.0

Breast carcinoma

 8 15.0

Metastatic carcinoma

 12 14.3

Lung carcinoma

 26 10.0

Immune response and other effects

VEGF may prevent immune response to tumours

Tumours have developed a variety of mechanisms to avoid immune responses. One of these mechanisms involves the inhibition of dendritic cells(Immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system), which are antigen-presenting cells that stimulate B cells and T cells. Recently, it has been demonstrated in vitro that VEGF can prevent the functional maturation of dendritic cells from their haematopoietic progenitors. Tumour secretion of VEGF may play an important role in suppressing the immune antitumoural response.13

VEGF has multiple other effects

The effects of tumoural expression of VEGF are currently being investigated in dendritic cells and haematopoietic stem cells.

History of VEGF and angiogenesis research

Timeline of research milestones14–27

 

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.

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(A hormone receptor specific to oestrogen that is found at high levels in some breast cancers; binding of oestrogen to ER can cause accelerated growth of these tumours), 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.

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(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour) 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.

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)

The role of Genentech and Roche in VEGF research

For over two decades, researchers at Genentech (now part of F. Hoffmann-La Roche Holding) led by Napoleone Ferrara have contributed to research in VEGF and angiogenesis. This journey of discovery was facilitated by a culture of both science and creativity at the company, where scientists are encouraged to spend a portion of their time on their own research interests. So, while Ferrara was originally hired to study the reproductive system, his interest in angiogenesis was allowed to flourish, leading to important discoveries in this new and exciting field.

Identification and isolation of VEGF

Hypothesising that mitogenic effect observed with endothelial cells (in a medium conditioned by bovine pituitary cells) was mediated by a secreted protein, Genentech researchers become the first to identify and isolate a new pro-angiogenic factor. Because the protein promotes the growth of only vascular endothelial cells, it is named VEGF.22

Purification and cloning of VEGF

Genentech researchers identify cDNA clones encoding 121-, 165-, and 189-amino acid molecular species of VEGF. The classical secretory signal sequence observed in these clones confirms that VEGF is, in fact, a secreted protein.28

Elucidation of the first VEGFR

Working with scientists from the University of California at San Francisco, Genentech researchers demonstrate that a recently discovered receptor on the surface of endothelial cells (FLT1) is a high-affinity receptor for VEGF.24

Characterisation of the role of VEGF in physiological angiogenesis

Having already contributed to the growing evidence implicating VEGF in tumour angiogenesis, Genentech researchers collaborate to show that VEGF is also required for embryonic vasculogenesis.26

In the years since these important discoveries, Genentech, in partnership with Roche, has maintained an ongoing commitment to basic research in this field and continues to explore the role of VEGF in many solid tumours, including colorectal, lung and breast cancers.

F. Hoffmann-La Roche established an alliance with Genentech in 1990. As of September 2009, Genentech forms an integral part of Roche.

Summary

As discussed in this section, angiogenesis is a critical process in tumour growth and development. The predominant regulator of this pathological process is VEGF. Produced in response to a variety of cellular and environmental stimuli, VEGF has been shown to facilitate survival of existing vessels, contribute to vascular abnormalities, and stimulate new vessel growth. Although researchers have learned a great deal about the role of VEGF in tumour biology, further investigation will continue to clarify how VEGF functions in the pathogenic development of tumours.

References

  1. Hicklin DJ, Ellis LM. J Clin Oncol 2005;23:1011–27.
  2. Ferrara N, Carver-Moore K, Chen H, et al. Nature 1996;380:439–42.
  3. Carmeliet P, Ferreira V, Breler G, et al. Nature 1996;4:435–9.
  4. Benjamin LE, Hemo I, Keshet E. Development 1998;125:1591–8.
  5. Jain RK. Science 2005;307:58–62.
  6. Jain RK. Nat Med 2001;7:987–9.
  7. Dvorak HF, Brown LF, Detmar M, et al. Am J Pathol 1995;146:1029–39.
  8. Senger DR, Galli SJ, Dvorak AM, et al. Science 1983; 219 (4587): 983-985
  9. Jain RK. Sci Am 1994;271:58–65.
  10. Jain RK. Cancer Res 1987;47:3039–51.
  11. Hashizume H, Baluk P, Morikawa S, et al. Am J Pathol 2000;156:1363–80.
  12. Jain RK. Cancer Metastasis Rev 1987;6:559–93.
  13. Gabrilovich DI, Chen HL, Girgis KR, et al. Nat Med 1996;2:1096–103.
  14. Ferrara N. Nat Rev Cancer 2002;2:795–803.
  15. Lewis WH. Johns Hopkins Hospital Bulletin 1927;41:156–62.
  16. Ide AG, Baker NH, Warren SL. Am J Roentgenol 1939;42:891–9.
  17. Algire GH, Chalkey HW, Legallis FY, Park HD. J Natl Cancer Inst 1945;6:73–85.
  18. Greenblatt M, Shubik P. J Natl Cancer Inst 1968;41:111–24.
  19. Ehrmann RL, Knoth M. J Natl Cancer Inst 1968;41:1329–41.
  20. Folkman J, Merler E, Abernathy C, Williams G. J Exp Med 1971;133:275–88.
  21. Senger DR, Galli SJ, Dvorak AM, et al. Science 1983;219:983–5.
  22. Ferrara N, Henzel WJ. Biochem Biophys Res Commun 1989;161:851–8.
  23. Plate KH, Breier G, Weich HA, Risau W. Nature 1992;359:845–8.
  24. de Vries C, Escobedo JA, Ueno H, et al. Science 1992;255:989–91.
  25. Terman BI, Dougher-Vermazen M, Carrion ME, et al. Biochem Biophys Res Commun 1992;187:1579–86.
  26. Ferrara N, Carver-Moore K, Chen H, et al. Nature 1996;380:439–42.
  27. Shweiki D, Itin A, Soffer D, Keshet E. Nature 1992;359:843–5.
  28. Leung DW, Cachianes G, Kuang WJ, et al. Science 1989;246:1306–9.

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