Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment

Figure 3

Summary of representative interactions between TAM, TAN, platelet, and tumor cells. The interactions between neutrophil and macrophages have not been significantly understood in the TME and the contribution of platelet in differentiation of TAM and TAN suggested in this review awaits further studies. Tumor cells, blood vessels, and CAF comprise TME. CCL2, CXCL12, CSF-1, SDF-1, complements, and SEMA3A for macrophage recruitment [30, 106]. CSF-1 prompts TAMs to produce EGF. The EGF-CSF-1 loop can be initiated by CAF derived factors, such as CXCL12 and HRGβ1 [106]. IL-4 from CD4+ T cells or tumor cells can activate macrophages to TAMs. CCL18 and osteonectin can increase migration and intravasation of tumor cells in metastasis. CXCL-8, CXCL15, and HMGB1 secreted from tumor cells can recruit TANs in metastatic sites. MPO and cytokines from neutrophil recruit platelet and macrophages. PAR and P2Y receptor are involved in thrombin and ADP mediated platelet activation, respectively. P-selectin is involved in platelet leukocyte tethering and leukocyte activation. α-granule is a storage of proteins that enhance adhesive process, angiogenesis, and extracellular matrix (ECM) degradation [81]. GPIIbIIIa mediates tumor cell and platelet interaction via vWF, fibronectin, and fibrinogen [80]. Red arrow: neutrophil-mediated recruitment of macrophages in tumor. Thick arrow: conversion of platelets, neutrophils, and macrophages to activated platelets, TAN, and TAM, respectively. GPIIbIIIa, glycoprotein IIbIIIa; vWF, Von Willebrand factor; ADP, adenosine diphosphate; PARs, proteinase-activated receptors; P2Y, P2Y receptors; TF, tissue factor; NE, neutrophil elastase; HMGB1, high mobility group protein B1; HRGβ1, heregulin β1.