Effects Of Aspirin And NS-398 On Proliferation And Angiogenesis-related Factors Of Gastric Cancer Cell Line SGC7901 In Vitro And In Vivo

Angiogenesis is an essential process for the primary tumor to grow, metastasis and invade into the adjacent normal tissues. Experimental and clinical evidences suggest that the processes of tumor growth and metastasis are angiogenesis-dependent. Tumor neovasculature is characterized by a tortuous architecture, irregular blood flow, and increased permeability relative to normal vessels. The degree of intratumoral microvessel density (MVD) by immunohistochemistry is thought to reflect the angiogenic activity generated by the neoplastic cells and the supporting stroma. Many reports have shown that increased angiogenesis was associated with poor prognosis for patients with various tumor types, including gastric cancer. Angiogenesis is a complex process controlled by a balance of angiogenic and angiostatic factors involved in multiple pathways that result in endothelial cell proliferation, differentiation, and organization into a functional network of vascular channels. The potential to block tumor growth by inhibition of the neoangiogenic process represents an intriguing approach to the treatment of solid tumors.Cyclooxygenase-1 and -2 (COX-1 and COX-2) are the rate-limiting enzymes that convert arachidonic acid to prostaglandins. COX-1 is a constitutively expressed enzyme that catalyzes the expression of prostaglandins, which control a variety of physiologicalfunctions, including gastric protection, renal blood flow, and platelet aggregation. COX-2 is an inducible enzyme and induced by inflammatory, mitogenic, growth factor, and cytokine signaling, which may cause overexpression of prostaglandins in inflammatory and malignant tissues. Numerous reports that show overexpression of the COX-2 protein in colonic, esophageal, and gastric carcinogenesis as well as breast, bladder, and prostate carcinogenesis have been published. Also, few reports have shown that COX-2 stimulates tumor angiogenesis by up-regulating VEGF in human colorectal and endometrial cancer. The effect of COX-2 on angiogenesis suggests its possible involvement in tumor progression.There is considerable evidence that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, reduce the risk of colorectal cancer and adenomas. Both epidemiological studies and experimental studies in animals have demonstrated the anticarcinogenic effects of these drugs, and randomized trials in patients with familial adenomatous polyposis have shown that sulindac and celecoxib can cause regression of adenomas. Population-based studies and case-control surveillance study also showed decreased incidence of gastric cancer in aspirin and other NSAIDs users. The mechanisms by which NSAIDs reduces the risk of gastric cancer are not clear. It was postulated that anti-angiogenesis effect might have a role.Gastric cancer is one of the most common malignancies in China. Gastric resection combined with chemotherapy and/or radiotherapy is the rational treatment. So far, there has been no report about the effect of aspirin on proliferation and angiogenesis on gastric cancer. Few researches focused on selective COX-2 inhibitors on apoptosis, angiogenesis and proliferation of gastric cancer. The current study was designed to investigate aspirin and a selective COX-2 inhibitor, NS-398, on the proliferation on gastric cancer cell line SGC7901 in vitro. Their effects on COX-2 and an angiogenic factor, vascular endothelial growth factor (VEGF) were also investigated. Angiogenesis of the gastric cancer xenografts in nude mice and the in vivo effects of aspirin and NS-398 on angiogenesis were investigated by immunohistochemistry. The studies were divided into three partslisted below:Part I: Effects of aspirin and NS-398 on the proliferation and cell cycle of gastriccancer cell line SGC7901 in vitro.Methods1. MTT assay was used to analysis the effect of Aspirin and NS-398 on SGC7901 cell viability and proliferation in vitro.2. Flow cytometry (FCM) was used to analysis the effect of aspirin and NS-398 on cell cycle parameters.3. Stastistical analysis: The...