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 lung cancer
"...high VEGF levels have been correlated with poor prognosis in patients with lung cancer..."
Herbst, et al. J Clin Oncol 20051
As observed in tumour(An abnormal growth of cells, forming a mass of tissue) malignancy(The tendency of a medical condition, especially tumours, to become progressively worse and to potentially result in death) in general, the process of angiogenesis, and in particular, VEGF, may play a critical role in tumour growth and metastasis(The spread of a disease from one organ or part to another non-adjacent organ or part) of lung cancer. It has been shown that
- VEGF is significantly associated with increased MVD in lung cancer.2
- VEGF is overexpressed in a majority of NSCLC tumours.3
- VEGF is expressed at higher levels as lung cancer progresses.4
- VEGF may be correlated with carcinogens in lung cancer.5
- VEGF overexpression(Excessive expression of a gene or its protein product) has been associated with decreased survival in lung cancer.2,6
In this section, you will find information on the prevalence of VEGF expression in lung cancer, the relationship between VEGF expression and PD, correlation of VEGF with carcinogens and VEGF as a prognostic factor in lung cancer.
Prevalence of VEGF-expressing tumours
Studies assessing VEGF expression in lung cancer utilise a variety of assay techniques and therefore prevalence rates may vary widely.
In general, however, VEGF has been shown to be expressed in the majority of NSCLC tumours.2,7
VEGF overexpression was demonstrated in a study of 88 patients with surgically resected NSCLC.3
VEGF overexpression in tumour types
| Tumour type | VEGF overexpression, % (n) |
|---|---|
| All NSCLCs Squamous cell carcinomas Adenocarcinomas Large-cell carcinomas |
77 (68/88) 75 (36/48) 73 (22/30) 100 (10/10) |
Interestingly, some NSCLC tumours appear to have a nonangiogenic phenotype(The visible characteristics of an organism that are produced by the interaction of the organism’s genes and the environment).
- In one study, Passalidou et al. reported that approximately 9% (nine of 113) of tumours showed no evidence of neovascularisation(The formation of functional microvascular networks with red blood cell perfusion).8
- It has been hypothesised that such tumours, which fill up in alveoli, acquire their blood supply from adjacent alveolar septa.8
In general, however, NSCLC tumours overexpress VEGF and are highly vascularised, and the intensity of vascularisation has been shown to correlate with the probability of metastasis.9
VEGF expression in NSCLC
Yuan et al. investigated the role of VEGF in NSCLC. This image shows immunohistochemical staining of a lung adenocarcinoma for VEGF. VEGF is mainly expressed in the cytoplasm of cancerous cells.2
Int J Cancer 2000;89:475–83. © 2000 International Union Against Cancer. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
VEGF expression: an important factor in lung cancer
VEGF overexpression, while not universal, is an important factor of lung cell tumours.
- In an analysis of 72 patients with NSCLC, Yuan and colleagues found VEGF mRNA(A molecule of RNA encoding a chemical 'blueprint' for a protein product) levels in tumour samples to be significantly higher than in adjacent normal tissue in 100% of cases (p<0.001).
They showed that adenocarcinomas had greater amounts of VEGF mRNA and were more likely to have high levels of VEGF protein compared with squamous(Denoting a surface tissue consisting of a single layer of flat scale-like cells) cell carcinomas, a factor that may contribute to the high metastatic(Pertaining to the spread of a disease, usually cancer, from one organ or part to another non-adjacent organ or part) potential observed with adenocarcinomas.2
In a separate study, Imoto et al. discovered VEGF to be expressed in the majority of tumours in 91 patients with completely resected stage I–III NSCLC.
- There was a statistically significant(Pertaining to an event that is unlikely to have occurred by chance) association between VEGF expression and microvessel counts in the tumour tissue, as microvessel counts were significantly higher in patients with VEGF-positive tumours than in patients with VEGF-negative tumours (p=0.01).
- Microvessel counts in this study were higher in patients with nodal metastases than in those without nodal metastases.7
Other studies have also shown a correlation between microvessel count and systemic metastases in NSCLC.9,10
VEGF in NSCLC
In a 2006 study, Eriksson et al. showed a statistically significant increase in serum VEGF levels from the time of diagnosis until the time of death in patients with NSCLC. This image shows serum VEGF and bFGF levels for a representative patient during treatment and until time of death.4
Reprinted with permission from Neoplasma 2006;53:285–90. http://www.neoplasma.sk/
One measure of the importance of VEGF throughout the natural history of lung cancer is its presence at various stages of disease.
In a recent study of 45 patients with stage III NSCLC, Eriksson and colleagues showed that there was a statistically significant (p=0.0004) increase in serum VEGF levels from the time of pathological diagnosis until the time of death.
- Serum VEGF and bFGF(Mitogenic growth factor that is widely utilised during wound-healing, growth and development) levels for a representative patient during treatment and until time of death are shown in the figure.
- The clinical significance of this finding is not yet known.4
VEGF expression and location of tumour vasculature
VEGF expression in various tumour locations
Research indicates that VEGF may be most highly expressed at the periphery of NSCLC tumours. Koukourakis et al. measured VEGF levels in normal lung tissue and in various sections of lung tumours, finding the highest levels of VEGF expression at the invasive fronts of the tumours. Legend: VEGF/KDR activation ratio obtained in lung tissue from normal individuals (A), in the normal lung distant (B) and adjacent (C) to the tumour-invading front, in the tumour-invading front (D), and in inner tumour areas (E).11
Reprinted with permission from the American Association for Cancer Research. Koukourakis MI, Giatromanolaki A, Thorpe PE, et al. Cancer Res 2000;60:3088–95.
The phenotype of vasculature within lung tumours has been shown to vary based on both location within the tumour and level of VEGF expression.
Specifically, research by Ushijima et al. in a retrospective analysis of samples from 255 stage I–III NSCLC patients showed a relationship between peripheral microvessel counts and poor prognosis, but did not find the same correlation with central microvessel counts.
- Patient survival was poorer when these peripheral vessels were associated with high levels of VEGF expression.12
- Similarly, Koukourakis and colleagues found that elevated microvessel counts localised on the advancing fronts of NSCLC tumours were also correlated with poorer outcomes.11,12
References
- Herbst RS, Onn A, Sandler A. J Clin Oncol 2005;23:3243–56.
- Yuan A, Yu CJ, Chen WJ, et al. Int J Cancer (Pred Oncol) 2000;89:475–83.
- Stefanou D, Batistatou A, Arkoumani E, et al. Histol Histopathol 2004;19:37–42.
- Eriksson P, Brattstrom D, Hesselius P, et al. Neoplasma 2006;53:285–90.
- Jarzynka MJ, Guo P, Bar-Joseph I, Hu B, Cheng SY. Int J Oncol 2006;28:337–44.
- Bremnes RM, Camps C, Sirera R. Lung Cancer 2006;51:143–58.
- Imoto H, Osaki T, Taga S, et al. J Thorac Cardiovasc Surg 1998;115:1007–14.
- Passalidou E, Trivella M, Singh N, et al. Br J Cancer 2002;86:244–9.
- Macchiarini P, Fontanini G, Hardin MJ, et al. Lancet 1992;340:145–6.
- Yamazaki K, Abe S, Takekawa H, et al. Cancer 1994;74:2245–50.
- Koukourakis MI, Giatromanolaki A, Thorpe PE, et al. Cancer Res 2000;60:3088–95.
- Ushijima C, Tsukamoto S, Yamazaki K, et al. Lung Cancer 2001;34:233–41.