Reappraisal of the Significance of Inducible Nitric Oxide Synthase inColorectal Cancer

Abstract

Backgrounds: Inducible nitric oxide synthase (iNOS), which produces high levels of nitric oxide (NO), is overexpressed in activated macrophages and some cancer cells. Although iNOS was thought to be involved in promoting colorectal cancer, contradictory reports supporting its tumoricidal effect exist. Methods: We first examined the iNOS enzyme activity in colorectal cancer tissue and immunohistochemical expression of iNOS in cancer cells and tumor-infiltrating macrophages. Then, association of iNOS activity or its protein expression was analyzed in relation to various clinicopathological covariates. Results: Four groups of patients were classified based on their iNOS expression status. Univariate and multivariate analyses showed that group 1 patients (low iNOS in both types of cells) and group 4 patients (high iNOS in both types of cells) had a shorter disease-free survival. Patients with extremely high or low iNOS enzyme activity tended to have a lower disease-free survival rate (p = 0.059). Conclusion: Macrophage/stroma-derived NO negatively regulates colorectal cancer development when cancer cells express low levels of iNOS, but might synergistically contribute to tumor progression in the presence of high levels of cancer-cell derived NO. The dual effects of NO should be considered in the design of anti-iNOS/NO therapy for colorectal cancer patients.