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. 2021 Mar 30;40(2):477–500. doi: 10.1007/s10555-021-09958-2

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — Mechanisms of tumor angiogenesis and lymphangiogenesis promotion by TAMs and TEMs. Effects of TAMs and TEMs on angiogenesis (a, b, c) and lymphangiogenesis (d). a TAMs and TEMs promote tumor angiogenesis via secreted factors [5]. EC-derived Ang-2 enhances the pro-angiogenic phenotype of TEMs [58, 102]. b TAMs and TEMs promote tumor angiogenesis via the secretion of protease. TAMs secrete MMP-9, cathepsin B, and cathepsin S, whereas TEMs secrete high level of MMP-9 [58, 103–105]. MMP-9 increases VEGF-A bioavailability via ECM degradation [106, 107]. Cathepsin S is involved in the degradation of anti-angiogenic proteins and in the formation of pro-angiogenic peptides via ECM degradation [108]. The promotion of angiogenesis by cathepsin B occurs via the induction of VEGF expression by cancer cells [109, 110]. All together, these proteases lead to an increase and a decrease of pro-angiogenic factor and anti-angiogenic factor in the TME, respectively, which promote tumor angiogenesis. c Upper panel: Vascular mimicry structures are perfused non-endothelial channels. They are formed by cancer cells in several cancer types, and promote tumor growth, metastasis, and angiogenesis [111, 112]. TAMs promote, at least in vitro, the formation of vascular mimicry channels by cancer cells [113, 114]. Lower panel: TAMs can directly form vascular mimicry structures in tumors [115]. d Upper panel: TAMs promote tumor lymphangiogenesis via the secretion of VEGF-C, VEGF-D, and LCN2 [116–118]. Furthermore, podoplanin-expressing macrophages (PoEMs) are able to interact with tumor LECs and are strongly involved in the promotion of tumor lymphangiogenesis [119–121]. This interaction is dependent on GAL8 (LECs), podoplanin, and β1 and β4 integrins (PoEMs) [119, 121]. The secretion of Semaphorin 7A by cancer cells promote the expression of podoplanin by TAMs [120]. Lower panel: TEMs and a subset of TAMs (called M-LECP) are able to integrate into pre-existing lymphatics, which promotes tumor lymphangiogenesis [122, 123]. This figure was created with BioRender.com