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. 2021 Jun 10;6:218. doi: 10.1038/s41392-021-00641-0

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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 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. 2 — TGF-β signaling pathway-mediated crosstalk between CAFs and cancer cells. The canonical TGF-β signaling pathways consist of TGF-β/Activin/Nodal-Smads pathway and bone morphogenetic protein/growth differentiation factor/Müllerian-inhibiting substance (BMP/GDF/MIS)-Smads pathway. Noncanonical pathways represent those that activate TGF-βR, but induce no-Smads pathway. Within tumor microenvironment (TME), a large number of TGF-β protein secreted by cancer cells mediated the transformation of NFs into CAFs supporting cancer progression by activation TGF-β signaling pathway, particularly canonical pathway. Activated CAFs can be orchestrated by TME to maintain their status and promote their proliferation and migration. In turn, these adaptations would also be contributed to the formation of tumor-promoting TME. CAF-secreted factors regulated extracellular matrix (ECM) remodeling to accelerate cancer invasion and metastasis indirectly. On the other hand, most factors derived from CAFs can directly mediate intricate regulation on the cancer cells. Most proteins, such as ECM proteins, GDF, TGF-β, IL-11, and CXCL12, could activate the pathway of cancer cells to exert biological functions, including promoting cancer growth, migration, invasion, and metastasis, through receptor–ligand binding. Genetic information would also transfer from CAFs into cancer cells by extracellular vehicles. CAF-derived exosomal miR-93 and miR-423 would be endocytosed by cancer cells and then promoted cancer chemoresistance and radioresistance. FOXA1 forkhead box protein A1, MMP2 matrix metalloproteinase 2, GP130 glycoprotein 130, CTGF connective tissue growth factor, IDH3α isocitrate dehydrogenase-3α, CAV-1 caveolin-1