Figure 3.

CAF activation pathways and downstream effects. CAFs are derived from multiple cell types and activated by multiple molecules including hedgehog (Hh), transforming growth factor-β (TGF-β), reactive oxygen species (ROS), interleukin-1β (IL-1β), fibroblast growth factor (FGF), platelet-derived growth factor (PDGR), stromal cell-derived factor 1 (SDF-1), heparin binding growth factor (HBGF) which can be driven by hypoxia. Precursor cells including mesenchymal stem cells (MSCs) are a source of CAFs activated by CXCL-12 and TGF-β derived from tumour cells. Pericytes, fibrocytes, stellate cells and adipocytes are also recruited by tumours by CXCL-12 and TGF-β, and are activated by TGF-β and PDGF. CAFs can derive from mature epithelial cells that differentiate into functional CAFs by TGF-β mediated epithelial-mesenchymal transition (EMT). Endothelial cells undergo EndoMT to differentiate into CAFs through TGF-β and SMAD signalling. HIF and TGF-β have a role in the function of CAFS. Genes associated with changes in ECM remodelling, metabolic reprogramming, angiogenesis, immune response and metastasis are direct transcriptional targets of HIF in CAFs or cancer cells. This creates bi-directional communication between CAFs and cancer cells through release of cytokines and chemokines (blue dots) which promotes proliferation of both cells, and further enhancement of pro-tumorigenic pathways (Adapted from (181, 182)). Created with BioRender.com.