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

Nicotine and oestradiol promote VEGF secretion by NSCLC tumours

Lung cancer is strongly linked to a known carcinogen – tobacco smoking.

  • Preclinical research indicates that expression of VEGF may be one way in which cells react to nicotine, a component of tobacco.

Jarzynka and colleagues studied the exposure of mice with xenograft bronchioloalveolar carcinoma(The medical term for a malignant tumour consisting of transformed epithelial cells, but include transformed cells of unknown cell lineage or origin) to oestradiol, nicotine, or both.

  • Mice exposed to both oestradiol and nicotine developed significantly larger tumours than control animals and their tumours had significantly higher increases in MVD.
  • Mice exposed to nicotine alone demonstrated higher MVD as well, but this difference was not statistically significant(Pertaining to an event that is unlikely to have occurred by chance).
  • As stated by the investigators, "These results suggest that oestradiol and nicotine may act in concert to stimulate angiogenesis(The growth of new blood vessels from pre-existing vessels) in vivo."

As with MVD, VEGF expression was also shown to correlate with exposure to oestradiol and nicotine together.

  • Individually, nicotine increased VEGF expression slightly, while a greater increase was seen with oestradiol alone.
  • The clinical significance of these findings is unknown.1

VEGF and prognosis in lung cancer

Several studies have shown that VEGF is associated with poor prognosis in lung cancer.2–4

Outcome Study type and size Source
Poor survival Clinical study (n=72)
Meta-analysis of 16 studies
 Yuan, et al. Int J Cancer (Pred Oncol) 20002
Bremnes, et al. Lung Cancer 20063
Malignant pleural effusion Clinical study (n=35) Yeh, et al. Oncogene 20065

VEGF and malignant pleural effusion in lung cancer

The role of VEGF in malignant pleural effusion

Patients with lung cancer who develop malignant pleural effusion have shorter survival compared with patients without effusion.

  • In an effort to determine 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 malignant pleural effusion in NSCLC, Yeh and colleagues performed both preclinical and clinical studies.
  • Their preclinical work, which included both tumour(An abnormal growth of cells, forming a mass of tissue) cell line and animal model experiments, examined the pathogenesis of malignant pleural effusion.
  • One protein they showed to be involved in this pathogenic process is Stat3.
  • In a tumour cell line study, the investigators also found that VEGF overexpression(Excessive expression of a gene or its protein product) was correlated with expression of Stat3.5

The investigators' clinical studies included a comparison between patients with malignant pleural effusion caused by NSCLC (n=23) and patients with non-malignant pleural effusion, that is, pleural effusion caused by CHF(A condition in which the heart's function as a pump is inadequate to deliver oxygen-rich blood to parts of the body, which become congested with fluid) (n=12).

  • In this comparison, VEGF levels were significantly higher in patients with lung cancer-related pleural effusion than in patients with non-malignant pleural effusion (p<0.0001).5

VEGF and survival in lung cancer

VEGF is associated with decreased patient survival

Yuan and colleagues demonstrated that high VEGF expression is correlated with a decreased rate of survival in patients with NSCLC.

  • In their study of 72 patients with stage I–III NSCLC, patients whose tumours expressed high levels of VEGF had a significantly shorter median survival following surgical resection than patients with low VEGF-expressing tumours (16.0 vs 45.0 months, p<0.001).
  • This relationship held true even after results were stratified(The process of dividing members of the population into homogeneous subgroups before sampling) for tumour stage (see figure below).2

MVD and survival in lung cancer

Like VEGF overexpression, microvessel count has also been correlated with a range of tumour characteristics and outcomes in lung cancer, including tumour size and metastasis(The spread of a disease from one organ or part to another non-adjacent organ or part), cancer recurrence and overall and disease-free survival.2,6–8

  • In one of the largest studies evaluating the relationship between angiogenesis and survival in lung cancer, Fontanini and colleagues prospectively assessed samples from 407 stage I–III NSCLC patients.
  • In a multivariate analysis that also assessed tumour size and regional lymph node(Bodies of lymphoid tissue located along the course of lymphatic vessels; involved in the filtration of lymph) status as prognostic variables, they found that increased MVD was strongly associated with poorer survival (p<0.00001).9

In 2006, Bremnes and colleagues conducted a meta-analysis of 16 studies of patients with either small cell lung cancer or NSCLC.

  • Their analysis confirmed that both VEGF expression and MVD are prognostic factors for poor survival, with a HR(An estimate of relative risk of an event occurring) of 1.8–2.0 for MVD and 1.5 for tumoural VEGF expression.
  • Note that a HR >1 indicates a poorer prognosis.3

References

  1. Jarzynka MJ, Guo P, Bar-Joseph I, Hu B, Cheng SY. Int J Oncol 2006;28:337–44.
  2. Yuan A, Yu CJ, Chen WJ, et al. Int J Cancer (Pred Oncol) 2000;89:475–83.
  3. Bremnes RM, Camps C, Sirera R. Lung Cancer 2006;51:143–58.
  4. Sandler AB, Johnson DH, Herbst RS. Clin Cancer Res 2004;10:4258s–62s.
  5. Yeh HH, Lai WW, Chen HH, Liu HS, Su WC. Oncogene 2006;25:4300–9.
  6. Imoto H, Osaki T, Taga S, et al. J Thorac Cardiovasc Surg 1998;115:1007–14.
  7. O'Byrne KJ, Koukourakis MI, Giatromanolaki A, et al. Br J Cancer 2000;82:1427–32.
  8. Kaya A, Ciledag A, Gulbay BE, et al. Respir Med 2004;98:632–36.
  9. Fontanini G, Lucchi M, Vignati S, et al. J Natl Cancer Inst 1997;89:881–6.

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