Fig. 1.

Routes of TAM recruitment and processes of monocyte maturation. (A) Glioma stem cells (pink) deposit periostin in the tumor stroma (green cells represent glioma cells), where it serves as a chemoattractant to infiltrating (M2-like) TAMs. (B) VEGFA and semaphorin 3A (Sema 3A) released by the tumor cells activate neuropilin-1 (NRP1), triggering the activation of VEGFR1 and subsequent recruitment of TAMs. (C) IL-34 derived from tumor cells mediates attachment of monocytes to the endothelial layer of blood vessel via CSF-1R binding on the surface of peripheral monocytes. IL-33, released from perivascular pericytes via PDGF-BB-PDGFRβ-Sox7 signaling also serves as a chemoattractant to peripheral monocytes. Likewise, macrophage inhibitory factor (MIF) and intercellular adhesion molecule 1 (produced by neural glial antigen 2+ pericytes) provide guiding signals to monocytes during extravasation. (D) Hypoxic stress enhances tumor microenvironment levels of sialic acid (SA), which decreases CD45 dimer signaling, increases CD45PTP (CD45 phosphatase), and inhibits STAT3 signaling in recruited monocytes, triggering differentiation of the TAM phenotype. (E) Notch signaling triggers maturation of vascular cell adhesion molecule 1+ monocytes.