Nitric oxide and metastatic cell behaviour

Abstract

Nitric oxide (NO) is a pleiotropic signalling molecule that subserves a wide variety of basic cellular functions and also manifests itself pathophysiologically. As regards cancer and its progression, however, the reported role of NO appears surprisingly inconsistent. In this review, we focus on metastasis, the process of cancer cell spread and secondary tumour formation. In a 'reductionist' approach, we consider the metastatic cascade to be made up of a series of basic cellular behaviours (such as proliferation, apoptosis, adhesion, secretion migration, invasion and angiogenesis). We evaluate how NO controls such behaviours, in comparison with normal cells. The available information suggests strongly that NO signalling would be expected to regulate these behaviours both positively and negatively and this probably leads to the observed apparent variability in the NO status of cancer cells and tissues. Thus, the role of NO in cancer is more complex than previously thought. A number of suggestions are made, including consideration of novel mechanisms, such as ion channels, in order to achieve a more consistent and integrated understanding of NO signalling in cancer and to realise its clinical potential.

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

“…Inhibition of the metastasis-inducer Snail and induction of the metastasis-suppressor RKIP Stavroula Baritaki, 1 Sara Huerta-Yepez, 1,4 Anna Sahakyan, 1 Iordanis Karagiannides, 2 Kyriaki Bakirtzi, 2 Ali R. Jazirehi 3 and Benjamin Bonavida 1, that DETANONOate-induced inhibition of NFκB 33 may inhibit downstream the metastasis-inducer transcription factor Snail which in turn derepresses the expression of the metastasis-suppressor gene product, RKIP. Since both Snail and RKIP have been shown to regulate the EMT phenotype, [22][23][24][28][29][30][31] the DETANONOate-mediated effects on Snail and RKIP expressions and activities may lead to inhibition of EMT.…”

“…The biphasic role of NO in oncology seems to be dependent on its working microenvironment, including the responsiveness of the tumor type, the redox state of the reaction, as well as the final intracellular concentration and the duration of intracellular exposure to nitric oxide. [1][2][3] As such, abundant evidence in the literature suggests that low NO concentrations may act in tumor cells as enhancers of their survival, proliferation and growth by protecting them from apoptosis, whereas high NO concentrations the role of nitric oxide (No) in cancer has been controversial and is based on the levels of No and the responsiveness of the tumor type. It remains unclear whether No can inhibit the epithelial to mesenchymal transition (eMt) in cancer cells.…”

Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice

“…However, AG displayed an antimetastatic action on a model of inflammationbased murine fibrosarcoma progression, altering neither tumor incidence nor tumor growth [20] . Metastatic cell behavior could be positively or negatively regulated by nitric oxide, accordingly to iNOS and eNOS expression in endothelial cells, macrophages, stromal fibroblasts and cancer cells [21] . In an attempt to explain the observed A: Time of spontaneous death of mice was determined, Kaplan-Meier survival curves were plotted and median survival was calculated.…”

Targeting nitric oxide for cancer therapy

“…• has been shown to have potent influences on many of the key characteristics that define the metastatic phenotype of cancer cells including motility, adhesion and invasion (recently reviewed by Williams & Djamgoz 2005). The effect of NO…”

“…• on motility of leucocytes has been widely studied and both stimulatory and antagonistic actions have been reported (Williams & Djamgoz 2005). There is also information on tumour cell migration.…”