Nitric oxide and tumor biology

Sonveaux, Pierre [UCL] Feron, Olivier [UCL]

Nitric oxide (NO) has dichotomous activities in many areas of biology. NO can promote cell survival but also has pro-apoptotic effects. It can stimulate cell growth as well as cell death and necrosis. As a potent vasodilator, NO regulates the vasodynamic balance, but it can also promote angiogenesis, which is associated with the loss of vasoactivity. These apparent contradictory roles have been widely exemplified, leading to the conclusion that the net effect of NO depends on its available concentration in a determined environment (characterized by redox status, the level of reactive oxygen species (ROS), metal ions, specific proteins, and target cell type). In vivo, low levels of NO (picomolar to nanomolar range) are produced by the constitutively expressed NO-synthase (NOS) isoforms, endothelial and neuronal NOS (eNOS and nNOS, respectively) (Figure 18.1). Under calcium activation, these enzymes produce a transient increase in NO levels that control important physiological processes such as vasodilation (eNOS) and neuronal transmission (nNOS). Constitutive NOS activation can further be prolonged upon post translational modifications. Changes in the eNOS phosphorylation status (see below) can, for instance, drive the enzyme toward pro-angiogenic capacities (sustained nanomolar levels of NO). In contrast to the constitutive isoforms, iNOS, the inducible NOS, is expressed under some pathological conditions and generates micromolar NO concentrations (Figure 18.1). It has been demonstrated that iNOS is induced by several agents involved in the inflammatory process, including lipopolysaccharides (LPS) and other bacterial products, cytokines, such as tumor necrosis factor-alpha [TNF-α] and interferongamma [IFN-γ), and viral proteins. During host defense, NO generated by iNOS in macrophages behaves as a cytotoxic agent that alters protein integrity and function through S-nitrosylation and induces a variety of phenomena including caspase activation, lipid peroxidation, DNA damage and inhibition of mitochondrial respiration, all leading to cell damage and most often cell death. The genotoxic effects of NO have been attributed to its reaction with oxygen and superoxide to form peroxynitrites and other reactive nitrogen species (RNS) that produce either direct or indirect DNA damage. iNOS itself can produce both NO and superoxide simultaneously, suggesting that their combination to form peroxynitrites could readily happen at the time of synthesis.8 Although iNOS is easily induced and expressed in macrophages, many other cell types express iNOS during inflammation or under comparable stresses. Thus, based on the previously mentioned general observations, the role of endogenous NO in cancer should mainly be determined by the level of NO production, itself dependent on the nature of the NOS isoform activated. Accordingly, cell transformation would preferentially be fostered by iNOS expression through the selection of immunopreserved clones bearing RNS or ROS-induced DNA lesions, and eNOS would, instead, participate in the later phase of angiogenesis that supports exponential tumor growth (Figure 18.1). This chapter discusses the fact that although these general assumptions are somehow verified, NO bioactivity and its effects are further determined by the cellular nature and microenvironment of the tumor where it is produced.