Expression of Nitric Oxide Synthase Isotypes in Advanced Gastric Carcinoma

ABSTRACT

BACKGROUND: Increased expression of nitric oxide synthase (NOS) isotypes is present in human tumor cell lines and solid tumor tissues. Hypoxia upregulates NOS expression, and nitric oxide (NO) induces mitogenesis among endothelial cells. NO has been known to induce vascular endothelial growth factor (VEGF) expression in carcinoma cells and to induce neovascularization in tumors. METHODS: The expression and cellular localization of 3 isotypes of NOS was detected by immunohistochemistry in 73 advanced gastric carcinoma tissues along with adjacent normal gastric mucosa; and the relationship to known clinicopathologic parameters, microvascular density, and VEGF expression was analysed. RESULTS: Forty-four (60.3%), 56 (76.7%), and 52 (71.2%) of the 73 cases revealed eNOS, nNOS, and iNOS expression, respectively. Intestinal type adenocarcinomas tended to have higher activity of eNOS (p=0.000) and nNOS (p=0.001) activities than did the diffuse type adenocarcinomas. All isotypes of NOS (eNOS, p=0.001; nNOS, p=0.005; iNOS, p=0.044) tended to be highly expressed when the tumor was differentiated. There was no significant relationship between any of the 3 NOS isotypes and microvascular density, whereas VEGF was closely related with microvascular density (p=0.000). The expression of VEGF was not related to with any of the NOS isotype expressions. CONCLUSIONS: From the above results, we speculated that NO may be implicated in the early stage of the gastric carcinogenesis rather than the growth and progression stages, and NO does not appear to affect angiogenesis or VEGF expression in the advanced gastric carcinoma.