Fig. 1

The origins and related activating pathways of cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME). CAFs are derived from multiple cell types through the following distinct mechanisms: A Tissue-resident fibroblasts and quiescent stellate cells are converted into CAFs by the stimulation of modulators including transforming growth factor-beta (TGF-β), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2 (FGF-2), stromal-derived factor-1 (SDF-1), reactive oxygen species (ROS) and insulin-like growth factor 1 (IGF-1) as well as the deficiency of vitamin A; B The trans-differentiation progress of mesenchymal stem cells (MSCs) into CAFs contain epithelial-mesenchymal transition (EMT) along with the recruitment and activation induced by various stimulating molecules such as TGF-β1, C–C chemokine ligand 2 (CCL2), C–C chemokine ligand 5 (CCL5), C-X-C chemokine ligand 12 (CXCL12) and tumor-derived exosomes; C Adipocytes together with pericytes and smooth muscle cells can transdifferentiate into CAFs by TGF-β1 and Wnt3a; D Endothelial cells are transformed into CAFs through endothelial-to-mesenchymal transition (EndMT); E Epithelial cells are transformed into CAFs through epithelial-to-mesenchymal transition (EMT); F Monocytes are transformed into CAFs through monocyte-to-myofibroblast trans-differentiation (MMT)