Fig. 1

The origins of cancer-associated fibroblasts (CAFs). CAFs are a population of heterogeneous cells of multiple origins that originate mainly via the following mechanisms: a tissue-resident normal fibroblasts and quiescent stellate cells are activated into CAFs when stimulated by factors such as transforming growth factor-β (TGF-β), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2 (FGF2), sonic hedgehog (SHH), bone morphogenetic protein (BMP) and reactive oxygen species (ROS); b mesenchymal stem cells are recruited by cytokines and chemokines secreted into the tumor microenvironment, such as TGF-β, CXCR6, CXCL16, CXCL12, CCL2 and CCL5; c other cells such as pericytes, adipocytes and smooth muscle cells are transdifferentiated into CAFs; d endothelial cells are transformed into CAFs via endothelial-to-mesenchymal transition (EndoMT); and e epithelial cells are transformed into CAFs via epithelial-to-mesenchymal transition (EMT)