Janus-Faced Tumor Microenvironment and Redox

Abstract

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. Antioxid. Redox Signal. 21, 723-729.

Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation

“…Finally, and particularly in the case of tumors, they must often accomplish these tasks within the confines of hypoxic, acidotic and nutrient-deprived environments (4). The point at which these activities and conditions become rate limiting for growth can vary among different tumor types and even within the same tumor over relatively short times and distances (5) thus requiring tumors to accommodate to often conflicting metabolic demands.…”

Poly-arginine conjugated triarylmethyl radical as intracellular spin label

“…However, intracellular pH, redox status and GSH level provide complementary information of particular importance to physiology and pathology of various diseases such as cancer[9]. Recently, we synthesized a cell-permeable trityl radical AMT-02 (Figure 1) which contain biodegradable acetoxymethyl esters.…”

Methemoglobin as a redox-responsive nanocarrier to trigger the in situ anticancer ability of artemisinin

“…Using bio-inspiration from the antimalarial mechanism of ART in nature, here we explored methemoglobin (MHb)-an oxidized form of hemoglobin with iron in the ferric state (Fe 3+ ) rather than in the ferrous state (Fe 2+ )-as a smart nanocarrier for hydrophobic ART. While MHb reacts very slowly with ART, 14,15 the upregulated reducing capacity [16][17][18][19] of the tumor tissue can work as an excellent biogenic trigger to reduce ferric iron in MHb to the ferrous state, activating its ability to generate free radicals and resulting in the cytotoxicity of ART in situ (Scheme 1).…”