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. Author manuscript; available in PMC: 2020 Feb 10.
Published in final edited form as: Annu Rev Physiol. 2019 Feb 10;81:535–560. doi: 10.1146/annurev-physiol-020518-114721

Figure 2.

Figure 2

The role of macrophages in tumor lymph angiogenesis. Adhesion of circulating VEGFR3+ monocytes to tumor BECs in response to cancer cell (and stromal cell) secreted IL-8 (blue circles) favors monocyte extravasation. Once inside the tumor parenchyma, monocyte differentiation into TAMs, which in human tumors are mostly CD163+, elicits their production of VEGFA, VEGFC, and VEGFD (purple circles) upon TNF-α/TNFR1 signaling (yellow circles depict TNF-α). Autocrine stimulation of VEGFR3 by its cognate ligands VEGFC and VEGFD further increases VEGFC production. VEGFA, VEGFC, and VEGFD as well as MMPs, uPA, and plasmin favor the migration of tip-LECs and the formation of new lymphatic sprouts. They also contribute to the junction disassembling of LECs and thus to the promotion of cancer cell intravasation through the lymphatics. TEMs are in close in proximity to the tumor lymphatics but not in lymphatics of normal tissue. These perilymphatic macrophages (that share other lymphatic markers such as PROX-1, LYVE-1, PDPN, and VEGFR3) support new sprout growth in a paracrine manner, but it is still debated if they can integrate into the vessel wall. Chemotherapy will also act on TAMs and induce the initiation of a cathepsin B/heparinase cascade that leads to enhanced VEGFC release by TAMs and thus lymph angiogenesis and cancer cell intravasation. Mirroring this, radiotherapy induces the release of CSF1 (orange circles) by cancer cells that boosts the recruitment and differentiation of VEGFR3+ (prolymph angiogenic) TAMs. Abbreviations: BEC, blood endothelial cell; CSF1, colony-stimulating factor 1; IL-8, interleukin 8; LEC, lymphatic endothelial cell; LYVE-1, lymphatic vessel endothelial hyaluronan receptor 1; MMP, matrix metalloproteinase; PDPN, podoplanin; PROX-1, prospero homeobox protein 1; TAM, tumor-associated macrophage; TEM, Tie2-expressing macrophage; Tip-LEC, lymphatic endothelial tip cell; TNF-α, tumor necrosis factor-alpha; TNFR1, tumor necrosis factor receptor 1; uPA, urokinase-type plasminogen activator; VEGFA, vascular endothelial growth factor A; VEGFC, vascular endothelial growth factor C; VEGFD, vascular endothelial growth factor D; VEGFR3, vascular endothelial growth factor receptor 3.