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. Author manuscript; available in PMC: 2016 Apr 1.
Published in final edited form as: Trends Immunol. 2015 Mar 11;36(4):240–249. doi: 10.1016/j.it.2015.02.005

Figure 1. Hypoxia mediates recruitment of angiogenic myeloid cells that drive both tumor progression and resistance to antiangiogenic therapy.

Figure 1

Solid tumors eventually reach a size that, due to oxygen and nutrient diffusion limits, cannot be sustained by the existing vasculature. This results in a decrease in oxygen tension within the tumor. Hypoxia positively regulates the expression of a variety of genes in tumor cells, many of which result in the infiltration or accumulation of angiogenic myeloid cells. For example, tumor-derived VEGF, CSF-1, MCP-1, and SDF1α recruit angiogenic monocytes including macrophages and Gr1+ G-MDSC and MMDSC into tumors; CXCL2 recruits angiogenic neutrophils and monocytes; Ang2 recruits angiogenic Tie2-expressing monocytes and macrophages (TEMs); IL-4 and IL-6 induce the differentiation of infiltrating monocytes into angiogenic and immune-suppressive macrophages; also, Sema3A brings Nrp1-expressing TAMs into hypoxic regions where they are reprogrammed to an angiogenic and immune-suppressive phenotype. Tumor-associated MDSC, TAM, TEMS, and neutrophils then secrete or liberate sequestered angiogenic factors, of which VEGF is dominant to facilitate neovascularization. This in turn leads to continued tumor growth and disease progression. Blocking persistent vessel growth can blunt tumor growth; however, this increases hypoxia and hypoxia-induced gene expression. Thus, tumors reinitiate the recruitment of angiogenic MDSC, TAM, TEMS, and neutrophils via the secretion of hypoxia- regulated factors, many of which drive myeloid-cell recruitment during normal tumor progression. These cells then reinstatement tumor angiogenesis via VEGF-independent pathways, thereby conferring tumor resistance to VEGF-blockade. Abbreviations: VEGF, vascular endothelial growth factor; Sema3A, semaphorin-3A; MCP-1, monocyte chemotactic protein-1; CSF-1, colony stimulating factor-1; CXCL2, (C-X-C motif) ligand 2; IL-6, interleukin-6; IL-4, interleukin-4; Ang2, angiopoietin 2; SDF1α, stromal-derived factor 1α; GCSF, granulocyte colony stimulating factor; PlGF, placental growth factor; G- or M- MDSC, granulocytic or monocytic myeloid-derived suppressor cell; TAN, tumor-associated neutrophil; TAM, tumor-associated macrophage; TEM, Tie2+-expressing macrophage.