Expressions of COX-2 and VEGF-C in gastric cancer: correlations with lymphangiogenesis and prognostic implications

Abstract

Background: Cyclooxygenase-2 (COX-2) has recently been considered to promote lymphangiogenesis by up-regulating vascular endothelial growth factor-C (VEGF-C) in breast and lung cancer. However, the impact of COX-2 on lymphangiogenesis of gastric cancer remains unclear. This study aims to test the expression of COX-2 and VEGF-C in human gastric cancer, and to analyze the correlation with lymphatic vessel density (LVD), clinicopathologic features and survival prognosis.

Methods: Using immunohistochemistry, COX-2, VEGF-C and level of LVD were analyzed in 56 R0-resected primary gastric adenocarcinomas, while paracancerous normal mucosal tissues were also collected as control from 25 concurrent patients. The relationships among COX-2 and VEGF-C expression, LVD, and clinicopathologic parameters were analyzed. The correlations of COX-2, VEGF-C and level of LVD with patient prognosis were also evaluated by univariate tests and multivariate Cox regression.

Results: The expression rates of COX-2 and VEGF-C were 69.64% and 55.36%, respectively, in gastric carcinoma. Peritumoral LVD was significantly higher than that in both normal and intratumoral tissue (P < 0.05). It was significantly correlated with lymph node metastasis and invasion depth (P = 0.003, P = 0.05). VEGF-C was significantly associated with peritumoral LVD (r = 0.308, P = 0.021). However, COX-2 was not correlated with VEGF-C (r = 0.110, P = 0.419) or LVD (r = 0.042, P = 0.758). Univariate analysis showed that survival time was impaired by higher COX-2 expression and higher peritumoral LVD. Multivariate survival analysis showed that age, COX-2 expression and peritumoral LVD were independent prognostic factors.

Conclusions: Although COX-2 expression was associated with survival time, it was not correlated with VEGF-C and peritumoral LVD. Our data did not show that overexpression of COX-2 promotes tumor lymphangiogenesis through an up-regulation of VEGF-C expression in gastric carcinoma. Age, COX-2 and peritumoral LVD were independent prognostic factors for human gastric carcinoma.

Figure 1

Immunohistochemical staining of Cox-2 in the gastric carcinoma: the positive expression of COX-2 protein was stained as yellow or brownish yellow in the cytoplasm of carcinoma cells (LsAB, ×400).

Figure 2

Immunohistochemical staining of VEGF-C in the gastric carcinoma: the positive expression of VEGF-C protein was stained as yellow or brownish yellow in the cytoplasm of carcinoma cells (LsAB, ×400).

Figure 3

Immunohistochemical staining of D2-40: Immunoreactivity of D2-40 proteins was found in the cytoplasm and cellular membrane of lymphatic endothelial cells. A. Detection of lymphatic vessels in the peritumoral tissue of gastric carcinoma was highlighted by immunostaining against D2-40 (LsAB,×200). B. Immunohistochemical staining of D2-40 in the intratumoral tissue of gastric carcinoma (LsAB, ×200). C. Immunohistochemical staining of D2-40 the normal gastric mucosal tissue (LsAB, ×200).

Figure 4

Kaplan-Meier overall survival curves for 56 patients with gastric carcinoma patients with COX-2 positive expression had a significantly worse OS compared with those with COX-2 negative expression.

Figure 5

Kaplan-Meier overall survival curves for 56 patients with gastric carcinoma: patients with VEGF-C expression had no association with survival time of gastric carcinoma.

Figure 6

Kaplan-Meier overall survival curves for 56 patients with gastric carcinoma: patients with high peritumoral LVD had a significantly worse OS compared with those with low peritumoral LVD.