Nitric oxide: Immune modulation of tumor growth

Nitric oxide (NO) plays a pivotal role in the physiology of diverse tissues including cells of the immune system. It is well established that the levels of nitric oxide must be regulated carefully to maintain homeostasis. Dysregulation or overproduction of nitric oxide has been implicated in the pathogenesis of many disorders including atherosclerosis, neurodegenerative diseases, autoimmune diseases, and cancer. Tumor-associated generation of NO, predominately via inducible nitric oxide synthase (iNOS), can be produced by the immune-system (dendritic cells, NK cells, mast cells, monocytes, macrophages, Kupffer cells) as well as by other cells involved in tumor growth. Depending upon the levels of NO generated, the potential exists for it to behave like a "double-edged" biological sword. In tumorigenesis assays, both protective and toxic effects of NO generated from immune cells frequently are seen in parallel. Thus, there is no simple, uniform picture of the function of NO in the immune modulation of tumor growth. The striking inter- and intracellular signaling between tumor cells and immune system cells makes it extremely difficult to predict the effect of NOS inhibitors and NO donors. This complexity has delayed evaluation of NO regulatory drugs as frontline therapies for cancer.