Figure 3.

CAF “education” by the cancer-derived factors (extension of section C) in Figure 2). Cancer-derived exosomes carry elements such as miRNA and lncRNA that promote the transformation of NAF to CAF through downstream signals that include cascades such as TGF-β/Smads, JAK/STAT, NF-κB, and MAPK. NAF-CAF conversion may also be driven by the reprogramming of glucose metabolism and the HIF-1α signalling pathway involved in glycolysis. Both the canonical TGF-β signalling pathway (TGF-β/Smads) and the non-canonical pathway (with activation of TGF-β but not Smads) are actively involved in the malignancy of NAFs. In CAFs, while miRNA-21 can attenuate the inhibition of PTEN on PDK1/AKT, the receptor–ligand binding-activated PI3K can promote it. As a result, through the PDK1/AKT signalling cascade mTOR protein is transported into the nuclei, and subsequently, the mTOR protein regulates the expression of targeted genes associated with CAFs differentiation. Notch signalling pathway is also involved in CAF differentiation via AKT. In turn, CAF-mediated PI3K/AKT signalling pathway regulates cell proliferation, migration, and stemness in cancer cells. EGFR/ERK signalling in CAFs is stimulated by E2 and G1 and upregulates fatty acids metabolism. Further, PDGF-BB and SDF-1 stimulate a higher invasive and migratory capability of CAFs via ERK1/2 phosphorylation (Table 1).