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. 2020 Jun 18;5:99. doi: 10.1038/s41392-020-0205-z

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© The Author(s) 2020

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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — Positive regulation among cancer cells, leukocytes, and neurons to cancer progression. Cancer cells release neurotrophins and extracellular vesicles to activate the neurogenic/axonogenic switch and release chemotactic factors while expressing ligands in the membrane to recruit and activate the immunosuppressor switch in the tumor microenvironment for reciprocally stimulate the cancer cells and the angiogenic process. Cancer-associated nerves release peptides (sensorial fibers) and neurotransmitter as NA or ACh (autonomic fibers) stimulating proliferation and migration of cancer cells, but they also recruit and activate immunosuppressor leukocytes as M2-macrophages and MDSCs. Leukocytes release pain mediators and stimulate to nerves, but also release neurotrophins, inducing tumor innervation. Protumor factors are released by leukocyte populations promoting cancer cell proliferation, migration, and metastasis. Joint of cells activate the angiogenic switch, via angiogenic growth factors released by cancer cells and leukocytes as mast cells or M2 macrophages, and by sympathetic-derived noradrenaline. NA noradrenaline, ACh acetylcholine, VEGF vascular endothelial growth factor, BDNF brain-derived neurotrophic factor, SDF-1 Sema4D: semaphorin 4D, Sema4F semaphorin 4F, PGE₂ prostaglandin E₂. EV extracellular vesicles