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.
Highlights
Nitric oxide (NO) is a short-lived ubiquitous molecule that regulates numerous physiological processes in the cardiovascular, nervous, and immune systems [1]
We demonstrated that activated macrophages usually expressed higher levels of inducible NO synthase (NOS) (iNOS) than cancer cells, and the homeostasis between lower iNOS in tumor cells and high iNOS in macrophages might determine the destiny of tumor progression
Expression of iNOS was higher in macrophages than in most tumor cells, supporting that high levels of NO synthesized by macrophages are cytotoxic/ cytostatic to tumor cells
Summary
Nitric oxide (NO) is a short-lived ubiquitous molecule that regulates numerous physiological processes in the cardiovascular, nervous, and immune systems [1]. Three isoforms of NOS have been identified: neuronal NOS (nNOS); endothelial NOS (eNOS); and inducible NOS (iNOS) [2]. NNOS and eNOS are constitutively expressed in neuronal cells and vascular endothelial cells and are calcium dependent. INOS is not usually expressed in healthy quiescent cells, but is rapidly transcriptionally induced in activated cells ( macrophages) in response to stimulation with bacterial products and inflammation-associated cytokines. Increased iNOS expression with sustained NO levels has been reported in a number of human cancers: breast, prostate, bladder, esophagus, and colon [7,8,9,10,11,12,13,14]. Expression of iNOS was positively correlated with increased tumor angiogenesis, vascular invasion, decreased lymphocyte response, metastasis, and a poor prognosis. There is, a contradictory report that decreased expression of iNOS was associated with increasing tumor stage and decreased patient survival [11,12,13,14,15]
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