fig3
Figure 3. CAFs maintain the stemness of CSCs via secreted proteins. CAFs secrete a panel of proteins, including HGF, IL-6, IL-8, CLCF1, WNT5A, STC1, AREG, FGF2, OPN, IGF-II, and LIF, which can be recognized by corresponding receptors on the CSCs and subsequently maintain the stemness of CSCs via the STAT3, PI3K/AKT, NOTCH, and other pathways. Cancer cells-derived TGF-β promotes the activation of CAFs and the secretion of DAN family BMP antagonist (GREM1), which, in turn, activates YAP/TAZ pathways in CSCs. CAFs: Cancer-associated fibroblasts; CSCs: cancer stem cells; HGF: hepatocyte growth factor; IL-6: interleukin-6; IL-8: interleukin-8; CLCF1: cardiotrophin-like cytokine factor 1; WNT5A: Wnt family member 5A; STC1: stanniocalcin-1; AREG: amphiregulin; FGF2: fibroblast growth factor-2; OPN: osteopontin; IGF-II: insulin-like growth factor 2; LIF: leukemia inhibitory factor; STAT3: signal transducer and activator of transcription 3; PI3K/AKT: phosphatidylinositol 3-kinase/protein kinase B; NOTCH: neurogenic locus notch homolog protein; TGF-β: transforming growth factor-β; DAN: deoxyribonucleic acid; BMP: bone morphogenetic protein; GREM1: gremlin-1; YAP/TAZ: Yes1-associated transcriptional regulator/transcriptional co-activator with PDZ-binding motif; SOX2/9: SRY (sex determining region Y)-box 2/9; POU5F1: POU class 5 homeobox 1, also known as octamer-binding transcription factor 4 (OCT4); NANOG: Nanog homeobox; CBX4: chromobox homolog 4; CXCL6: chemokine (C-X-C motif) ligand 6; CREB1: CAMP responsive element binding protein 1; MAML: Mastermind-like; CSL: C-promoter binding factor 1, Suppressor of Hairless/Lin-12, and Glp-1 phenotype; NICD: Notch intracellular domain; JAK: janus kinase; LIFRβ: leukemia inhibitory factor receptor β; ROR2: receptor tyrosine kinase-like orphan receptor 2; FZD: Frizzled; ERBB2: erb-b2 receptor tyrosine kinase 2; GPR77: G protein-coupled receptor 77; RSK: ribosomal S6 kinase; SMAD: mothers against decapentaplegic homolog.
