Angiogenesis plays an important role not only in non-neoplastic diseases such as diabetic retinopathy and arthritis^{1, 2)}, but also in the growth and metastasis of malignant neoplasms³⁾. It has been known that such substances as transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) are involved in angiogenesis and are secreted by tumor cells, vascular endothelial cells and inflammatory cells^4–6).

VEGF, in particular, increases the vascular permeability such that the plasma protein can easily leak out of the vessels^{7, 8)}, and the permeated plasma protein induces proliferation of tumor cells and vascular endothelial cells by forming fibrin gel^{9, 10)}. Many studies have reported that VEGF expression is associated with the malignancy of tumors. There have been reports in Korea on the association of VEGF expression with angiogenic status, malignancy and survival rate in breast cancer¹¹⁾, stomach cancer¹²⁾ and lung cancer¹³⁾. However, the results were not all consistent. Moreover, there was no effect on the patients who did not receive surgery, since most of the studies determined VEGF expression by using the immunochemical staining of the neoplastic tissue. A recent study has reported that serum VEGF (sVEGF) concentration is significantly correlated with intratumoral VEGF and intratumoral microvessel density, stating that sVEGF concentration could be used as a prognostic indicator for angiogenic status of tumors¹⁴⁾. Accordingly, we have closely examined whether sVEGF concentration can be used as a biological prognostic factor for lung cancer by evaluating the correlation of sVEGF concentration with histologic type, stage, and survival rate in patients with lung cancer.

Analysis of the two groups showed that the mean sVEGF concentrations were 341 pg/mL in the low-concentration group and 1,400 pg/mL in the high-concentration group (p < 0.05) (Table 1). There were no significant differences between the two groups in terms of age, sex, histologic type and stages. The high-concentration group did have longer smoking records and higher levels of C-reactive protein with no significant (p=0.43, p=0.44).

The sVEGF concentrations showed no significant difference by stage, but they tended to increase for non-small cell lung cancer patients as the stages progressed (Figure 1). For small cell lung cancer patients, the sVEGF concentration was high in the limited stage compared to the extensive stage, which was not significant (671 pg/mL vs. 579 pg/mL, p=0.72). While mean sVEGF concentration was 782 pg/mL in adenocarcinoma, 680 pg/mL in squamous cell carcinoma, and 605 pg/mL in small cell lung cancer, with adenocarcinoma being the highest, there was no significant difference within each histologic type (Figure 2). Overall, the median survival period for the 86 patients was 13.8 months, with 55% surviving for more than one year. The median period of survival for the low-concentration group was 13.9 months and 13.3 months for the high-concentration group, showing nosignificant difference between the two groups (p=0.86) (Figure 3).

Many studies have reported that VEGF expression is evidently involved in the angiogenesis of tumor cells. VEGF expression has also been associated with malignancy as well as the survival rate of some malignant tumors^{15, 16)}. In addition, some animal experimental models have shown that angiogenesis and tumor cell growth increased with VEGF administration^{17, 18)} while injecting anti-VEGF antibodies¹⁹⁾. Inhibited tumor growth. In a study on patients with lung cancer, Tamura et al.¹⁴⁾ reported that sVEGF concentration was higher in patients with lung cancer than in the normal controls and was correlated with intratumoral VEGF, stating that sVEGF concentration is an indicator for angiogenic status of tumor cells. In another study, sVEGF concentration decreased significantly after chemotherapy in a response group while no-response group with lung cancer exhibited no change²⁰⁾. However, in this study, sVEGF concentration displayed a tendency to increase with stage progression, while it registered no significant difference in each of the stages. At the same time in the survival rates between the low-concentration and high-concentration groups were relatively similar. The mean sVEGF concentration for of the patients was 686 pg/mL higher than other previous studies, as 81% of the patients were above stage IIIB.

The association of VEGF expression with angiogenic status and prognosis of lung cancer has been controversial. Some studies reported that VEGF correlated with angiogenesis but didnot associated with neoplastic proliferation in squamous cell carcinoma²¹⁾, whereas increased VEGF expression was associated with high angiogenic status and poor prognosis in adenocarcinoma²²⁾. This study revealed that sVEGF concentration was high in adenocarcinoma in comparison with other histologic types, if not significant, which was similar to the study by lmoto et al.²³⁾ that reported VEGF expression to be higher in adenocarcinoma than in squamous cell cacinoma. In a study on patients with small cell lung cancer, Salven et al.²⁴⁾ reported that prognosis was poor for patients with high sVEGF concentration or at the extensive stage prior to anti-cancer chemotherapy positing that sVEGF as well as stage was attributable to prognostic indication. However, our study showed that sVEGF concentration was relatively high for the limited stage, indicating that there was no correlation between sVEGF concentration and stage in small cell lung cancer patients.

These discrepancies are assumed to be due to the following reasons. First, angiogenesis is caused by interaction between various activators and inhibitors for angiogenesis, other than VEGF. Second, VEGF acts as an autocrine or paracrine growth factor, rather than an endocrine growth factor in malignant tumors therefore, sVEGF concentration is not an indicator for tumor growth and angiogenesis. Third, sVEGF concentration may be affected by leukocytes and C-reactive protein in such diseases as infection and chronic inflammation. Fourth, since 81% of the patients were over stage IIIB in this study, the survival rate rather than sVEGF concentration was greatly affected by the patient’s nutritional status, presence of accompanied diseases and remote metastasis.

Based on previous reports that VEGF expression correlates with the prognosis of lung cancer, we examined the correlation of sVEGF with stage, histologic type, prognosis and survival rate. However, we found that there was no correlation between them. Hence, we conclude that sVEGF concentration is not associated with the prognosis of progressive lung cancers, but further studies are needed for complete verification.