Janus-Faced Tumor Microenvironment and Redox

Significance: Tumor microenvironment (TME) is a complex term that includes extracellular matrix, blood vessels, endothelial, stromal, and inflammatory cells, and other supporting structures of the particular organ; and physiological components such as oxygen, pH, nutrients, waste products, signaling molecules, reducing/oxidizing species, growth factors, protumorigenic factors, etc. TME is now widely recognized as a major contributor to cancer aggression and treatment resistance and as a potential target for therapeutic intervention. Recent Advances: Among important physiological parameters of the TME, tissue hypoxia is considered to be a consequence of imbalanced angiogenesis and is associated with changes in metabolic pathways, including a higher dependence on glycolysis resulting in tissue acidosis. Both hypoxia and acidosis affect the tissue redox status and its key intracellular component, glutathione (GSH). Numerous publications support that these local TME conditions select for outgrowth of cells with appropriate phenotypes, which can reflect underlying genetics. Critical Issues: Here, we hypothesize that specific patterns of local TME, namely, tumor oxygenation, extracellular pH, redox, and GSH homeostasis, acting in orchestrated mechanism, can promote cancer cell survival, while at the same time being highly toxic and mutagenic for normal cells, thus contributing to the growth of cancers at the expense of the normal tissues they are invading. This review summarizes the experimental observations that support the hypothesized Janus-faced character of the redox axis. Future Directions: Normalizing the TME redox parameters may decrease the selection pressure for malignant phenotypes, therefore providing a tool for TME-targeted anticancer therapy.