Nitric oxide (NO) is an important signaling molecule in maintaining normal physiological processes like blood flow, neurotransmission and immune regulation. In cancer, it exhibits a dual role in context-dependent mechanism. At low levels, it activates angiogenesis, migration and tumor promotion; on the other hand, with an increase in concentration, it promotes apoptosis and has an anti-metastatic effect. Hence, regulated levels of NO are required to maintain normal hemostasis. NO has temporal and spatial regulation as its pro- and anti-metastatic effects are decided by the tumor stage, tumor microenvironment, and nitric oxide synthase isoforms expression. NO regulates EMT markers like upregulation of Snail, Twist, and ZEB1 (pro-EMT factors and downregulation of E-cadherin. NO also regulates the crosstalk between signaling factors, such as TGF-β, Wnt/β-catenin and NF-κB; during EMT and hypoxia-induced angiogenesis. NO promotes immunosuppression and metastasis by interacting with tumor-associated macrophages and myeloid-derived suppressor cells, which express iNOS. NO activates cancer promotion pathways like NF-κB, upregulates pro-metastatic genes (MMPs, cytokines), PI3K/Akt/mTOR and p53/Nrf2, along with regulating non-coding RNAs. Thus, NO is a potential target in cancer therapeutics and reviews focus on the new advancements using NO as a potential biomarker and therapeutic agent.
Seema Kumari (Sun,) studied this question.