The Role Of Cylooxygenase-2 And Vascular Endothelial Growth Factor-C Expression In The Development Of Lymph Metastasis In Gastric Cancer

Gastric carcinoma is one of the most common malignancies in the worldwide. Epidemiologic data indicated that death rates were approximately 50% lower among persons who used aspirin 16 tablets/month for 1 year, compared with those who used no aspirin. Cylooxygenase(COX), also referred to as prostaglandin endoperoxide synthase, is the rate-limiting enzyme in the production of prostaglandins(PGs) and a target for NSAIDs. Recently, two COX isoforms, COX-1 and COX-2, have been characterized. COX-1 is expressed constitutively in a number of cell types, whereas COX-2 is induced by a variety of cytokines, hormones, and tumor promoters and barely detected expression of COX-2 protein in normal tissues. COX-2 is strongly expressed in inflammation, tissues damage and cancer. Recently studies showed that COX-2 overexpression might enhance lymphatic invasion and metastasis in patients with gastric cancinoma. Moreover, lymph node metastasis is closely associated with existing of lymphatic vessels. Little is known about the biology of tumor lymphatic because of the lack of specific molecular markers. Just recently, however, novel markers for lymphatic endothelial cells have been identified and their availability has revolutionized research in this field. Vascular endothelial growth factor-c (VEGF-C) is a member of the VEGF/PDGF family and acts as highly specific lymphangiogenicfactor. Experimental studies with VEGF-C have shown that it can induce tumor lympyangiogenesis and direct metastasis to the lymphatic vessels and lymph nodes. Moreover, high overexpression of VEGF-C has recently been shown to closely correlate with the rate of metastasis to lymph node in cancer. In this study, immunohistochemistry and immunohistochemical double staining technique were used to investigate expression of COX-2, VEGF-C and lymphatic vessel density (LVD) in human gastric cancer and gastric normal mucosa. To compare the relationship among COX-2, VEGF-C, LVD and their relationship to other pathological variables, this may provide theoretical basis to study tumor lymphangiogensis and lymph node metastasis, and search for a new way to inhibit lymphangiogensis. Materials and Methods:1. Fifty-three patients who underwent surgery for gastric adenocancinoma at the First Affiliate Hospital of Zhengzhou University between 1997-2003, were included in the study. Samples were taken from tumor site and paracancerous tissues(^Scm), which were confirmed pathologically as normal gastric mucosa. None of the patients had received neoadjuvant chemotherapy or radiation therapy before surgery. Four-micron-thick sections were cut from formalin-fixed and paraffin-embedded tissue blocks.2. SP immunohistochemical technique was performed for detecting the expression of COX-2 protein and VEGF-C protein.3. An immunohistochemical double staining technique was utilized, using Vffl factor antibody in conjunction with a monoclonal antitype IV collagen antibody, to distinguish blood vessel from lymphatic vessel.4. The data were analyzed by software SPSS10.0, x2-test or two-sample t-test independent samples or Spearman correlation was used to compare difference between groups. A two-side P value of less than 0.05 was considered statistically significant.Results:1. The positive rate of COX-2 protein in gastric carcinomal cells was 62.3% and wasobserved diffusely throughout the cytoplasm and also observed in some interstitial cells and smooth mucosa fibril. The positive rate of COX-2 protein in the well-differentiated GC was 79.6%. The positive rate of COX-2 protein in the poor differentiated GC was 48.3%. Expressions of COX-2 protein in the well-differentiated GC were significantly higher than that in poor differentiated GC (P<0.05). In the group with lymph node metastasis and the group without lymph node metastasis, the positive rate of COX-2 protein expression was 75.8% and 40.0% respectively. There were significant differences between the two groups (P<0.05). The positive rate of COX-2 protein in early gastric cancer was 35.7%. The positive ra...