Serum vascular endothelial growth factor is related to systemic oxidative stress in patients with lung cancer

Summary

Vascular endothelial growth factor (VEGF) is known to play crucial role in tumour angiogenesis. It is demonstrated that VEGF can be up-regulated by oxidative stress. The aim of this study was to determine the serum VEGF levels and oxidative stress in patients with primary lung cancer and to investigate their association with clinicopathologic factors.

We measured serum VEGF levels and oxidative stress in 63 patients (age 63.02 ± 1.12 S.E.M.) with primary lung cancer before any treatment (39 NSCLC and 24 SCLC; 6 patients stage I, 3 stage II, 25 stage III and 29 stage IV) and 25 normal subjects. The serum VEGF levels were measured with enzyme linked immunosorbent assay. Serum oxidative stress levels were detected by a commercially available assay (D-ROMs test, Diacron, Grossetto, Italy).

The levels of oxidative stress in patients were higher than those in normal subjects (555.3 ± 30.35 UCarr vs. 360.1 ± 17.46 UCarr). Additionally, a significant difference was found in serum VEGF levels between lung cancer patients and healthy control subjects (428.1 ± 38.42 pg/ml vs. 298.8 ± 19.89 pg/ml, respectively, p = 0.040). Interestingly, serum oxidative stress presented a significant correlation with serum VEGF levels in patients with lung cancer (r = 0.542, p = 0.002). Serum VEGF levels were significantly associated with the clinical staging (N-stage) of the patients (p = 0.023), performance status (p = 0.004) and age (p = 0.004).

In conclusion, oxidative stress and VEGF are significantly increased in patients with primary lung cancer. The correlation between them might implicate new aspects of the mechanisms controlling tumour angiogenesis and may present clinical interest in the future. Further studies are warranted to evaluate the role of oxidative stress and VEGF as possible biomarkers for the diagnosis and follow-up of patients with lung cancer.

Introduction

Angiogenesis is important in the growth and progression of solid tumours and it has been suggested that disrupting tumour angiogenesis may disrupt tumour growth [1]. Tumour angiogenesis has been the subject of extensive research and is known to be involved in tumour development from the initial stages of cancer formation to the growth of distant metastases [2].

A major pro-angiogenic factor, vascular endothelial growth factor (VEGF), is a potent angiogenic cytokine that induces mitosis and also regulates the permeability of endothelial cells. VEGF stimulates endothelial cell proliferation and migration primarily through the receptor tyrosine kinase VEGF receptor 2 (Flk1/KDR). VEGF binding initiates tyrosine phosphorylation of KDR, which results in activation of downstream signalling enzymes including ERK1/2, Akt and eNOS, which contribute to angiogenic-related responses in endothelial cells [3], [4]. However, excessive VEGF expression in tumours promotes excessive permeability and may allow tumour cells to enter the blood stream and go on to metastasise [5], [6]. Furthermore, a relationship has been demonstrated between the development of a tumoural vascular network and VEGF levels in non-small cell lung carcinomas [7], [8]. Additionally, many studies have reported high levels of VEGF expression in lung cancer [9], [10]. It has been reported that overexpression of VEGF in tumour tissue represents an independent prognostic factor in patients with squamous cell lung cancer [11].

VEGF has been found to be up-regulated by conditions associated with the generation of free radicals and reactive oxygen intermediates (oxidants). However, underlying mechanisms are still not fully understood [12]. The imbalance between oxidants and antioxidants is referred to as oxidative stress. Free radicals damage DNA and thus may participate in mutagenesis and carcinogenesis [13]. Additionally, free radicals suppress Bcl-2 and enhance p53 expression and induce telomere shortening. In that way, the generation of adequate amounts of free radicals appears to be critical to trigger tumour cell apoptosis [14]. Furthermore, in several cancer types, including lung cancer, excess production of oxidative stress [15], [16] and elevated serum VEGF levels have been reported [17].

The aim of the present study was to evaluate serum VEGF levels and oxidative stress in patients with primary lung cancer, and to investigate a possible relationship between the two. Furthermore, possible associations between serum VEGF and oxidative stress levels with clinicopathologic factors were investigated.