Tumor microenvironment and nitric oxide: Concepts and mechanisms

The cancer tissue exists not as a single entity, but as a combination of different cellular phenotypes which, taken together, dramatically contribute to the entirety of their ecosystem, collectively termed as the tumor microenvironment (TME). The TME is composed of both immune and nonimmune cell types, stromal components, and vasculature—all of which cooperate to promote cancer progression. Not all immune cells, however, are immune-suppressive; some of them can promote the immune microenvironment to fight the invading and uncontrollably dividing cell populations at the initial stages of tumor growth. Yet, many of these processes and cellular phenotypes fall short, and the immune ecosystem more often than not ends up stabilizing in favor of the “resistant” resident cells that begin clonal expansion and may progress to metastatic forms. Stromal components, making up the extracellular matrix and basement membrane, are also not the most innocuous: CAFs embedded throughout secrete proteases that allow the onset of one of the most invasive processes—angiogenesis—through destruction of the ECM and the basement membrane. Vasculature formation, because of angiogenesis, is the largest invader of the TME and the reason metastasis happens. Vasculature is so sporadic and omnipresent in the TME that most drug therapies are mainly focused on stopping this uncontrollable process. As the tumor continues to grow, different processes are constantly supplying it with the ingredients favorable for tumor progression and eventual metastasis. For example, angiogenesis promotes blood vessel formation that will allow the bona fide escape of tumor cells to take place. Another process like hypoxia will present itself in several forms throughout the tumor (mild or acute, cycling or permanent), starting mechanisms such as epithelial to mesenchymal transitions (EMT) of resident cells and inadvertently placing the cells in such a stressful condition that production of ROS and DNA damage is unavoidable. DNA damage can induce mutagenicity while allowing resistant cells to survive. This is where drugs and treatments can subsequently suffer in effectiveness. Finally, another molecule has just surfaced as being a very important player in the TME: nitric oxide. Often overlooked and equated with ROS and initially assigned in the category of pathogenic molecules, nitric oxide can definitely do some damage by causing metabolic reprogramming and promotion of immunosuppressive phenotypes at low concentrations. However, its actions seem to be extremely dose-dependent, and this issue has become a hot target of current treatment goals. Shockingly, nitric oxide, although omnipresent in the TME, can have a positive effect on targeting the TME broadly. Thus, while the TME is a myriad of cellular phenotypes and a combination of different tumor-promoting processes, each process is interconnected into one whole: the tumor microenvironment.