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Figure 5: The brain tumor microenvironment, heterogeneous tumor zones and MIF actions. Conceptual framework depicting the metabolic and immune cell complexity of malignant brain tumors, (glioblastomas, GBM) is given as a simplified model classifying the tumor into three distinct tumor zones (TZ1–TZ3). Tumor Zone 1 (TZ1) consists of the main tumor—bulk and core glioma cells, corresponding to contrast enhancing regions in MRI images. MIF is mainly produced in TZ1 and secreted into the extracellular space. TZ2 represents the area of perifocal edema, which is characterized by its specific proangiogenic microenvironment and presence of transitory glioma cells. In addition, this tumor zone shows pronounced accumulation of microglial cells, which also infiltrate TZ1. TZ3 is the most awkward zone for therapeutic intervention, since this tumor zone consists mainly of healthy brain parenchyma. However, isolated glioma-initiating cells termed partisan cells colonize TZ3 and are most probably responsible for tumor recurrence following surgery. TZ2 is probably biologically most active, influencing TZ1 and TZ3 by tumor-derived metabolites impacting the immune system, angiogenesis, and cell fate.