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. 2021 Nov 12;39(1):159–179. doi: 10.1007/s10585-021-10120-z

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© The Author(s) 2021

Open AccessThis 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. 6 — An important contribution of tumor and LN lymphangiogenesis to cancer metastasis. A Normal lymphatic tissue drainage through lymphatic capillaries, collecting lymphatics, and LNs. B lymphangiogenic factors produced by premetastatic tumors, including VEGF-C, VEGF-D, VEGF-A, and HGF, are taken up by peritumoral lymphatic capillaries and are transported via the collecting lymphatics toward the tumor-draining SLN, where they act directly on preexisting lymphatic vessels to induce LN lymphangiogenesis. Tumor-draining lymphatic vessels display an enlarged size and increased lymph flow and pulsing. (C) Once metastatic tumor cells have spread to their draining LNs, they serve as a major

source of lymphangiogenic factors. These promote the remodeling and SMC rearrangement of distant (post-SLN) lymphatic vessels and lymphangiogenesis in distant LNs and promote secondary metastasis, including organ metastasis, via the thoracic duct, which connects to the venous circulation via the subclavian vein. CSC, cancer stem cell. The chemokines CCL21 and CXCL12, released by activated lymphatic endothelial cells (LECs) within SLNs, might provide a niche for cancer cells with stem cell–like properties that express the receptors CCR7 and CXCR4 [57]. Permission has been obtained to reproduce legend and figure for Fig. 6 from Journal of Clinical Investigation [57]