It is known that vascular endothelial growth factor (VEGF) family is an important role in vasculogenesis and angiogenesis. Among the VEGF family members, VEGF-A plays an essential role in angiogenesis. However, the significance of serum levels of other VEGF members (VEGF-C and -D) has been reported [1][2][3].
Firstly, Yamamoto et al. [4] reported that serum VEGF level was significantly elevated in some cancer patients including those of gastric cancer compared with control subjects. After their study, we determined the circulating level of VEGF 165 (VEGF-A) in gastric carcinoma patients as well as healthy individuals [5]. We demonstrated that serum VEGF concentration was significantly associated with tumor stage. Based on our findings, increased level of VEGF-A was associated with large tumor burden. It may be due to ongoing angiogenesis or neovascularization associated with increasing tumor burden.
Recently, I have read with great interest an article by Tsirlis et al.
[3] that evaluated circulating VEGF-C and -D levels in gastric carcinoma. Serum VEGF-C and -D levels were significant predictors for the presence of gastric cancer however, their study failed to show the relationship between the circulating VEGF-C and -D levels and tumor characteristics such as lymph node metastasis (LNM), tumor size (T) status, and stage. Although some studies have indicated that overexpression of VEGF is an independent prognostic factor in gastric cancer [1,6], studies on circulating levels of VEGF-C and -D have shown contradictory results [1][2][3]. In contrast to the study by Tsirlis et al., Wang et al. [1] showed that increased levels of VEGF were positively correlated to LNM.
VEGF-C, lymphangiogenic factor, can stimulate lymphangiogenesis [7]. Although VEGF-C and -D influence the lymphangiogenesis, the correlation of their serum levels with LNM is controversial [1][2][3]7]. Circulating VEGF-C level may be related to VEGF-C expression in patients with gastric cancer. It is indicated for why VEGF screening may be beneficial in gastric cancer receiving anti-angiogenic therapy to monitor the treatment effect.
According to the clinical and experimental data, migration of tumor cells into the lymph nodes is facilitating by lymphangiogenesis [7]. Although increase in lymphatic vessel density may increases the tumor cells to invade lymphatic vessels surface, lymphatic metastasis may not depend on generation of new vessels. The association of the serum VEGF-C and -D levels with LNM has shown contradictory results. This discrepancy may suggest that other factors play role in induction of lymphangiogenesis. VEGF-A has recently emerged as a strong promoter of inflammatory and tumor lymphangiogenesis. In addition to VEGF-C and -D, lymphangiogenic effect of VEGF-A has been shown [8]. Neutralizing VEGF-A may reduce the density of intratumoral lymphatic vessels and inhibit lymph node and lung metastasis. Besides VEGF-C and -D, targeting VEGF-A may suppress lymphatic metastases as well as hematogenous metastasis.