Elsevier

Lung Cancer

Volume 46, Issue 3, December 2004, Pages 293-298
Lung Cancer

VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2004.04.037Get rights and content

Abstract

Different vascular endothelial growth factor (VEGF) gene polymorphisms have been shown to result in different VEGF gene responsiveness to various stimuli and different capacity for VEGF protein production. In the present study, we examined four VEGF gene polymorphisms in thirty–six individuals with non-small cell lung cancer (NSCLC). Gene polymorphisms were correlated with the VEGF protein expression in cancer cells and the tumor angiogenic activity. The −2578C/C, −634G/G and −1154A/A and G/A alleles in the VEGF gene were linked with low VEGF expression, while the −2578C/A, the −634 G/C and the −1154G/G alleles were linked with high VEGF expression. Tumors with −2578C/C had a significantly lower vascular density (VD) compared to the −2578C C/A. Similarly, cases with the −634G/G VEGF polymorphism had a singinificanltly lower vascular density compared to the combined C/C and G/C groups. In addition, the −1154A/A polymorphism seemed to relate with poor vaccularization but the difference did not reach significance. It is concluded that inherited VEGF sequence variations, which characterize the tumor genome itself, are strong determinants of the molecular VEGF and VEGF-downstream phenotype of NSCLC. The large variation in angiogenicity between tumors of similar histologic morphology emerges as a consequence of the ‘parental’ VEGF gene ability to produce VEGF.

Introduction

The importance of vascular endothelial growth factor (VEGF) in the angiogenic process of human malignancies is well established [1]. VEGF is a major angiogenic factor in non-small cell lung cancer (NSCLC), defining poor postoperative outcome [2]. High VEGF expression and/or high angiogenic activity is noted in about 30–40% of NSCLC [3], [4]. The reason for such a divergence of VEGF expression and angiogenic status in tumors of similar histologic type and differentiation remains obscure. To date, several polymorphisms within the VEGF gene have been identified [5], [6], [7], and some of them have been correlated with a weak ability for VEGF protein production [6], [7], [8].

The present study shows that NSCLC patients with specific VEGF gene polymorphisms develop tumors with low VEGF expression and poor vascularization, suggesting that inherited VEGF sequence variations are strong determinants of the molecular VEGF and VEGF-downstream phenotype of NSCLC.

Section snippets

Materials and methods

Paraffin embedded tumoral and normal lung tissues, derived from 36 patients with non-small cell lung cancer treated by surgery alone, were retrieved from the archieves of the Department of Pathology, Democritus University of Thrace, Alexandroupolis, Greece.

Results

VEGF protein was strongly expressed in the cytoplasm of 12/36 (33%) lung carcinoma samples examined. Overall, the median % of cancer cells with strong VEGF expression in the 12 cases exhibiting VEGF reactivity was 70% (range 20–90). Using a 50% cut-off point (strong staining in more than 50% of cancer cells), tumors were divided in two groups: (a) negative/low (24 cases) and (b) high (12 cases) VEGF reactivity.

The ‘maximum vascular density’ ranged from 14 to 95 (median value 40, mean 45.5,

Discussion

The role of VEGF gene sequence variations for tumor development and progression remains unclear. In a study by Stevens et al., carriage of the −460/+405 VEGF polymorphism significantly altered the VEGF promoter activity in response to phorbol esters [10]. Howell et al. reported that VEGF −1154AA genotype define melanomas with less aggressive behavior (thinner vertical growth and less thick tumors) [11]. McCarron et al. observed that the VEGF −1154AA genotype is associated with a reduced risk

Acknowledgements

The study was financially supported in part by the Tumour and Angiogenesis Research Group.

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