Study On The Effects Of Cyclooxygenase-2 Expression And The Anti-cancer Effects Of Specific Cyclooxygenase-2 Inhibitors In Vivo In Gastric Carcinoma

Objective: To evaluate the expression of cyclooxygenase-2 (COX-2) in gastric carcinoma and its relationship with raicrovessel density (MVD) and clinical pathological features. To investigate the effects of NS-398 on the angiogenesis, cell apoptosis and proliferation of gastric carcinoma xenografts in immunosuppressed mice.Methods: Immunohistochemical stain was used for detecting the expression of COX-2 and CD34 in 46 resected specimens of gastric carcinoma. Paracancerous tissues were examined as control. The Relationship of microvessel density, clinicopathological features and cyclooxygenase-2 expression in human gastric cancer were evaluated. The immunosuppressed mice subrenal capsule model of human gastric carcinoma was established. Fourty female kunming immunosuppressed mice transplanted in subrenal capsule with fresh gastric carcinoma explants of twenty patients were randomly divided into two groups. The treatment group received alternate-day NS-398 solution at a dose of 10 mg/kgintraperitoneally and control mice received the same volume of NS. Two groups mice were killed after 7 consecutive days, cancerous tissues were embedded in paraffin for TUNEL and immunohistochemical staining. Cyclooxygenase-2 (COX-2), proliferating cell nuclear antigen(PCNA), vascular endothelial growth factor-C (VEGF-C) expression and microvascular density (MVD) of the xenograft tissue were detected by immunohistochemical staining technique.Cell apoptosis was detected by TUNEL. The proliferation labeling indices (Pis),the apoptotic indices(AIs) and the ratio of Als/Pis were measured simultaneously. Results: The rate of COX-2 expression in gastric cancers was significantly increased compared with that in paracancerous tissues. The overexpression of COX-2 in gastric carcinoma is well related to its lymph node metastasis, TNM stage, differentiation degree and depth of the invasion, but it did not correlate with the size of tumor, blood-borne metastasis, and peritoneal dissemination. The MVD values were correlated with COX-2 overexpression, lymph node invasion and the depth of invasion. The establishment of immunosuppressed mice subrenal capsule model of human gastric carcinoma was successful. The xenografts grew constantly within 8 days after SRCA in CTX mice and angiogenisis is observed, fnmunosuppress mice was probably superior to mice as a host of SRCA. The COX-2 and VEGF-C expression in carcinoma tissues treated with NS-398 were significantly lower than those in control group. The MVD values of treated with NS-398 was not significantlylower than those treated with NS. The apoptotic indices(AIs) in carcinoma tissues treated with NS-398 was significantly higher than those treated with NS. The proliferation labeling indices (Pis) treated with NS-398 was significantly lower than those treated with NS. The ratio of AIs/PIs in carcinoma tissues treated with NS-398 was significantly higher than those treated with NS. Conclusion: The expression of COX-2 may be play an important role in neovascularization and tumor progression. It may serve as a prognosis factor and the guide for clinical decisions. Mouse subrenal capsule transplantation is an acceptable short-term in vivo model in the study of tumor angiogenisis. NS-398 may suppress angiogenesis and lymphangiogenesis of gastric carcinoma xenografts in immunosuppressed mice via inhibiting COX-2 and reducing the expression of VEGF-C. NS-398 can markedly enhance apoptosis of gastric cancer cells and inhibits their proliferation. COX-2 may participate in VEGF-C lymphangiogenic pathway.