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

"The link between inactivation or suppression of the von Hippel-Lindau tumour(An abnormal growth of cells, forming a mass of tissue) suppressor gene and the resulting overexpression(Excessive expression of a gene or its protein product) of VEGF as a key step in the pathogenesis(The mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent) of renal cell carcinoma(The medical term for a malignant tumour consisting of transformed epithelial cells, but include transformed cells of unknown cell lineage or origin) has been well described."

Bukowski. Kidney Cancer J 20061

Recent advances in the understanding of the pathogenesis and molecular biology of RCC have identified angiogenesis as a key factor in the development of the disease. A major component of the angiogenic process in RCC is VEGF.2

In this section, you will find information on the implications of VEGF in RCC, including the unique role of VEGF and angiogenesis in RCC biology, evidence and prevalence of VEGF-expressing tumours and the potential role of VEGF as a prognostic factor.

Biology of RCC

Approximately 80% of RCCs have clear-cell histology i.e. cells appear clear under a microscope.5 In the majority of clear-cell RCCs, the VHL gene is inactivated through means such as deletion or other genetic mutation.2 

Under normoxic conditions(Pertaining to normal levels of oxygen), the pVHL closely regulates HIF-1α by causing its rapid degradation, so that HIF-1α is not normally found in the cell. As a result, HIF-1α is unavailable to bind to the corresponding subunit, HIF-1β, and the subsequent cascade of cellular signals does not occur.4 In contrast, under hypoxic conditions, pVHL regulation of HIF-1α is impaired. As a result, HIF-1α is not degraded. The resulting accumulation of HIF-1α within the cell is responsible for the high degree of vascularity commonly seen in VHL-deficient tumours.4 A critical consequence of VHL inactivation is upregulation(An increase in the number of receptors on the surface of target cells, making the cells more sensitive to a hormone or another agent) of VEGF via a pathway involving accumulation of HIF-1α.3,4,6 

Recent research also indicates that VHL silencing results in defects in a process called ubiquitination(The process of inactivating a protein by attaching ubiquitin to it. Ubiquitin is a small molecule that acts as a tag that signals the protein-transport machinery to transports the protein to the proteasome for degradation), in which cellular proteins (in this case, HIF-1α) are tagged for degradation with molecules known as ubiquitins.3 Impairments in the ubiquitination pathway lead to the accumulation of HIF-1α within the cell, even without hypoxic conditions.4 

HIF-1α is a key transcriptional factor in the molecular pathway of hypoxia and regulates the expression of a number of genes whose products are critical to tumour angiogenesis, proliferation(The reproduction of cells by multiplication of parts), survival and metabolism. With respect to angiogenesis in RCC, one of the most important gene products downstream of HIF-1α is VEGF.2–4,6

What is ubiquitination?

Ubiquitination is a cellular regulatory process in which proteins called ubiquitins are added to another, larger protein – the target protein. This process acts as a signal for the target protein to undergo degradation. Under normoxic conditions and with normal VHL function, the pVHL plays a role in the ubiquitination and subsequent degradation of HIF-1α.3,4,7

The unique role of VEGF in RCC pathogenesis

VEGF is a potent inducer of tumour angiogenesis.2,8 VEGF is expressed in many human cancers, but RCC in particular produces remarkably high levels, with tumours having a highly vascular histological appearance. The overexpression of VEGF in RCC is the direct result of inactivation of VHL gene. Data suggest that VHL inactivation occurs in the majority of clear-cell RCCs.2,4

Loss of pVHL expression results in constitutive expression of HIF-1α and induction of hypoxia-regulated genes, including those encoding for VEGF, PDGF-β and TGF-α.3 These gene products have been implicated in the malignant phenotype(The visible characteristics of an organism that are produced by the interaction of the organism’s genes and the environment) of RCC, which is characterised by hypervascular tumours, local and distant metastases via haematogenous spread, uncontrolled growth and resistance to apoptosis(The process of programmed cell death that may occur in multicellular organisms).2,4,8,9

The role of VEGF in particular has been explored as a key factor in the pathogenesis of RCC. VEGF functions to increase vascular permeability, induce endothelial cell proliferation and migration and promote endothelial cell survival. Thus, VEGF serves as a potent promoter of angiogenesis.2 Furthermore, VEGFR(Characterises the capacity of a blood vessel wall to allow for the flow of small molecules (ions, water, nutrients) or even whole cells (lymphocytes on their way to the site of inflammation) in and out of the vessel) expression has been observed in RCC cells, suggesting that VEGF may also serve as an autocrine stimulus in RCC.10

Evidence of VEGF expression in RCC

Angiogenesis is a major driving factor in the pathogenesis of RCC. The angiogenic phenotype occurs as a result of the high incidence of VHL loss, which leads to HIF dysregulation and a subsequent increase in pro-angiogenic factors.2,4 Thus, it would be expected that VEGF expression would be evident in RCC. Indeed, several investigators have confirmed this hypothesis by measuring VEGF expression either through mRNA(A molecule of RNA encoding a chemical 'blueprint' for a protein product) or protein levels. VEGF expression was observed in the vast majority of RCCs and several reports noted increased VEGF expression in tumour tissue compared with normal renal tissue.11–16 Together, these data demonstrate that VEGF is a key mediator of angiogenesis in RCC.

Prevalence of VEGF-expressing tumours

A number of investigators have examined RCCs to see whether VEGF is overexpressed. Their methods include the measurement of VEGF mRNA expression, as well as the measurement of VEGF protein levels. The results of six clinical studies show that the vast majority of RCCs express VEGF, underscoring the critical role of VEGF and angiogenesis in RCC.11–16

Prognostic implications of VEGF in RCC

Jacobsen et al. examined VEGF expression in 229 tumour samples from patients who underwent nephrectomy for RCC at various disease stages. The investigators reported correlation between VEGF expression and tumour size and tumour stage. More notably, they reported significantly decreased survival for patients whose tumours expressed VEGF, as measured by tissue microarray (p=0.011).8

In 74 RCC samples, Paradis et al. demonstrated that VEGF expression was significantly correlated with decreased survival.17 Furthermore, Yildiz et al. investigated the relationship between clinical outcomes and both microvessel invasion and VEGF expression in 48 RCC tumour samples. This group demonstrated a statistically significant(Pertaining to an event that is unlikely to have occurred by chance) correlation between microvessel invasion and death due to RCC (p<0.001). The investigators also observed that VEGF expression levels were significant negative predictors of survival in RCC (p<0.001).9

Summary: VEGF in RCC

RCC is a highly vascularised, VEGF-driven disease whose development is directly linked to VEGF overexpression and angiogenesis.18–20

Both translational and clinical research continue to offer a more in-depth understanding of the significance of angiogenesis and VEGF in RCC. The loss of function of VHL leads to VEGF expression and angiogenesis, a critical step in the pathobiology of RCC. Several reports have demonstrated the prevalence of VEGF expression in the vast majority of RCCs and still other reports have implicated VEGF as an important prognostic factor.

Further research is necessary to better define the relationship between prognosis and VEGF and angiogenesis in RCC.

The central role VEGF plays in the pathophysiology of RCC makes this disease a logical indication for therapy with the direct anti-VEGF inhibitor Avastin.

References

  1. Bukowski R. Kidney Cancer J 2006;4:16–18.
  2. Rini BI, Small EJ. J Clin Oncol 2005;23:1028–43.
  3. George DJ, Kaelin WG Jr. N Engl J Med 2003;349:419–21.
  4. Haase VH. Kidney Int 2006;69:1302–7.
  5. American Cancer Society. What is kidney cancer? Available at: http://www.cancer.org/Cancer/KidneyCancer/DetailedGuide/kidney-cancer-adult-what-is-kidney-cancer Accessed October 24, 2006.
  6. Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Proc Natl Acad Sci USA 1996;93:10595–9.
  7. Huang LE, Gu J, Schau M, Bunn HF. Proc Natl Acad Sci USA 1998;95:7987–92.
  8. Jacobsen J, Grankvist K, Rasmuson T, Bergh A, Landberg G, Ljungberg B. BJU Int 2004;93:297–302.
  9. Yildiz E, Gokce G, Kilicarslan H, Ayan S, Goze OF, Gultekin EY. BJU Int 2004;93:1087–93.
  10. Tsuchiya N, Sato K, Akao T, et al. Tohoku J Exp Med 2001;195:101–13.
  11. Hemmerlein B, Kugler A, Ozisik R, Ringert RH, Radzun HJ, Thelen P. Virchows Arch 2001;439:645–52.
  12. Lee JS, Kim HS, Jung JJ, Park CS, Lee MC. J Surg Oncol 2001;77:55–60.
  13. Na X, Wu G, Ryan CK, Schoen SR, di'Santagnese PA, Messing EM. J Urol 2003;170:588–92.
  14. Nicol D, Hii SI, Walsh M, et al. J Urol 1997;157:1482–6.
  15. Takahashi A, Sasaki H, Kim SJ, et al. Cancer Res 1994;54:4233–7.
  16. Tomisawa M, Tokunaga T, Oshika Y, et al. Eur J Cancer 1999;35:133–7.
  17. Paradis V, Lagha NB, Zeimoura L, et al. Virchows Arch 2000;436:351–6.
  18. Herbst C, Kosmehl H, Stiller KJ, et al. J Cancer Res Clin Oncol 1998;124:141–7.
  19. Jacobsen J, Grankvist K, Rasmuson T, et al. BJU Int 2004;93:297–302.
  20. Kaelin WG, Jr. Clin Cancer Res 2007;13:680s–4s.

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