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. 2021 Jan 4;20:2. doi: 10.1186/s12943-020-01294-3

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© The Author(s) 2020

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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 3 — Role of cytokines/chemokines on tumor progression and dissemination. High expression of CXCL12/CXCR4 axis in primary tumor cells or/and ECSCs enhances the activation of p-ERK-1/2 and increases these cells’ ability to invade and metastasize to lymph node and bone marrow. Abundant expression of CCL21 in the endothelium of lymphatic vessels and lymph nodes attracts CCR-7-positive tumor cells. CCL21/CCR7 axis upregulates MUC-1 expression through p-ERK signaling and enhances the migration, invasion, and lymph node metastasis through the lymphatic system. High production of potent angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors by primary tumor cells leads to a malignant process. Elevated levels of CXCL-8 secreted by primary tumor cells or TAMs induces the phosphorylation of AKT and ERK1/2 signaling pathway through the CXCR2 receptor expressed in primary tumor cells. These processes lead to further malignant progression to lymph nodes and distant organ metastasis through the lymphatic system and blood vessel. Also, circulating CXCL-8 contributes to the metastasis process