Figure 4.

Selenium availability in the tumor microenvironment influences the phenotype of macrophages. In a Se-deficient microenvironment TAMs lose glutathione dependent peroxidases (GPxs) and phagocytic activities (M1-like feature) toward transformed cells and produce PGE2 and TXA2 from arachidonic acid by cyclooxygenase (COX) supporting the highly glycolytic cancer stem cells (CSC). In the presence of selenium, TAMs rely on selenium importer SEPP1, and increase the selenoproteins which in turn polarize the macrophages toward an M2-like phenotype, with activation of PPARγ, degradation of pro-inflammatory PGE2, and production of Δ12-PGJ2. Δ12-PGJ2 activates the tumor suppressor protein p53, which in turn upregulates the TCA cycle and oxidative phosphorylation and lowers glucose uptake by the cells. As a compensatory mechanism the antioxidant machinery (selenium dependent thioredoxin reductases TrxRs and glutathione peroxidases GPxs) is enhanced but the increase is not sufficient to control ROS production. In a Se-rich microenvironment, its lower uptake might be assumed as one of the mechanisms through which neoplastic cells modulate M2-like macrophages and/or sustain TAMs function. In parts the figures are based on speculations and have been prepared by assembling in-house built cellular metabolic pathway outlines with a modified and adapted version of BioRender images.