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Initiation of malignant tumors is associated with a sustained state of chronic inflammation. In the initial stage of tumorigenesis, the first activated immune cells are usually the tissue-resident macrophages. In glioma, these cells are mainly represented by microglial cells. 2 Activated microglial cells generate high levels of O 2 radicals that induce genomic mutations and enhance interleukin (IL)-6 and tumor necrosis factor production supporting tumor cell survival. Recruitment of peripheral monocytes enhances this initial response. Various tumor cell-derived factors work together with hypoxia and trigger monocyte recruitment. For example, glioma stem cells produce periostin, an extracellular matrix component that provides interactive binding sites to V3 integrins on the cell surface of peripheral monocytes and M2-like TAMs to promote extravasation and migration in the glioma environment (Fig. Hypoxia can also trigger activation of vascular endothelial growth factor receptor 1 (VEGFR1) and neuropilin-1 (NRP1) in monocytes, leading to chemotaxis in, for instance, glioma and breast cancer. Likewise VEGFA and semaphorin 3A (Sema 3A) 6 released by the tumor cells, including glioma, 7 can activate NRP1, triggering the activation of VEGFR1 and subsequent recruitment of TAMs in glioma 8-10 (Fig.
Zhu et al. (Fri,) studied this question.